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BioRxiv : the Preprint Server For... Jun 2024It is not clear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in clinical or...
UNLABELLED
It is not clear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in clinical or preclinical development. TB is the deadliest infectious disease globally and more efficacious vaccines are needed to reduce this mortality. However, the immune correlates of protection for either preventing infection with or preventing TB disease have yet to be completely defined, making the advancement of candidate vaccines through the pipeline slow, costly, and fraught with risk. Human-derived correlate of risk (COR) gene signatures, which identify an individual's risk to progressing to active TB disease, provide an opportunity for evaluating new therapies for TB with clear and defined endpoints. Though prospective clinical trials with longitudinal sampling are prohibitively expensive, characterization of COR gene signatures is practical with preclinical models. Using a 3Rs (Replacement, Reduction and Refinement) approach we reanalyzed heterogeneous publicly available transcriptional datasets to determine whether a specific set of COR signatures are viable endpoints in the preclinical pipeline. We selected RISK6, Sweeney3 and BATF2 human-derived blood-based RNA biosignatures because they require relatively few genes to assign a score and have been carefully evaluated across several clinical cohorts. Excitingly, these data provide proof-of-concept that human COR signatures seem to have high fidelity across several tissue types in the preclinical TB model pipeline and show best performance when the model most closely reflected human infection or disease conditions. Human-derived COR signatures offer an opportunity for high-throughput preclinical endpoint criteria of vaccine and drug therapy evaluations.
ONE SENTENCE SUMMARY
Human-derived biosignatures of tuberculosis disease progression were evaluated for their predictive fidelity across preclinical species and derived tissues using available public data sets.
PubMed: 38948876
DOI: 10.1101/2024.06.21.600067 -
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 -
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 -
Cancer Innovation Feb 2024Since RNA sequencing has shown that induced pluripotent stem cells (iPSCs) share a common antigen profile with tumor cells, cancer vaccines that focus on iPSCs have made...
BACKGROUND
Since RNA sequencing has shown that induced pluripotent stem cells (iPSCs) share a common antigen profile with tumor cells, cancer vaccines that focus on iPSCs have made promising progress in recent years. Previously, we showed that iPSCs derived from leukemic cells of patients with primary T cell acute lymphoblastic leukemia (T-ALL) have a gene expression profile similar to that of T-ALL cell lines.
METHODS
Mice with T-ALL were treated with dendritic and T (DC-T) cells loaded with intact and complete antigens from T-ALL-derived iPSCs (T-ALL-iPSCs). We evaluated the safety and antitumor efficiency of autologous tumor-derived iPSC antigens by flow cytometry, cytokine release assay, acute toxicity experiments, long-term toxicity experiments, and other methods.
RESULTS
Our results indicate that complete tumor antigens from T-ALL-iPSCs could inhibit the growth of inoculated tumors in immunocompromised mice without causing acute and long-term toxicity.
CONCLUSION
T-ALL-iPSC-based treatment is safe and can be used as a potential strategy for leukemia immunotherapy.
PubMed: 38948536
DOI: 10.1002/cai2.95 -
Crohn's & Colitis 360 Apr 2024In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes...
BACKGROUND
In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results.
METHODS
We compared both documents and critically appraised the changes and implications for future clinical trials.
RESULTS
The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to "normal appearance of mucosa," which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term "mucosal healing" has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy.
CONCLUSIONS
The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.
PubMed: 38948490
DOI: 10.1093/crocol/otae038 -
Endoplasmic reticulum stress and quality control in relation to cisplatin resistance in tumor cells.Frontiers in Pharmacology 2024The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly... (Review)
Review
The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly sensitive to disturbances that lead to ER stress. In response, the unfolded protein response (UPR) activates to restore ER homeostasis, primarily through three sensors: IRE1, ATF6, and PERK. ERAD and autophagy are crucial in mitigating ER stress, yet their dysregulation can lead to the accumulation of misfolded proteins. Cisplatin, a commonly used chemotherapy drug, induces ER stress in tumor cells, activating complex signaling pathways. Resistance to cisplatin stems from reduced drug accumulation, activation of DNA repair, and anti-apoptotic mechanisms. Notably, cisplatin-induced ER stress can dualistically affect tumor cells, promoting either survival or apoptosis, depending on the context. ERAD is crucial for degrading misfolded proteins, whereas autophagy can protect cells from apoptosis or enhance ER stress-induced apoptosis. The complex interaction between ER stress, cisplatin resistance, ERAD, and autophagy opens new avenues for cancer treatment. Understanding these processes could lead to innovative strategies that overcome chemoresistance, potentially improving outcomes of cisplatin-based cancer treatments. This comprehensive review provides a multifaceted perspective on the complex mechanisms of ER stress, cisplatin resistance, and their implications in cancer therapy.
PubMed: 38948460
DOI: 10.3389/fphar.2024.1419468 -
Integrated Pharmacy Research & Practice 2024Warfarin plays an important role in anticoagulation therapy despite the availability of the newest oral anticoagulants, and achieving optimal anticoagulation is...
PURPOSE
Warfarin plays an important role in anticoagulation therapy despite the availability of the newest oral anticoagulants, and achieving optimal anticoagulation is challenging due to its narrow therapeutic range and variable dose. This study aimed to highlight polypharmacy and drug interactions in patients receiving warfarin therapy at Medani Heart Centre, Sudan.
METHODS
This retrospective hospital-based study was conducted from May 2017 to October 2018. Each concurrent medication prescribed for 104 patients was collected and checked for drug-drug interactions using Medscape Reference-Drug Interaction Checker. The data were analysed by using SPSS 20, and descriptive statistics were used.
RESULTS
The results revealed that 95.2% of patients had more than three medications in their profile, (3-5), (6-9) and more than 10 medications were prescribed for 40.4%, 44.2% and 10.6% of patients, respectively. A total of 93.3% of patients had drug-drug interactions, as follows: (1-5), (6-10), (11-15), (16-20) and more than 20 drug-drug interactions were found in 31.7%, 32.7%, 19.2%, 5.8% and 3.8% of patients, respectively. A total of 178 warfarin-drug interactions were identified in 88.5% of the patients. The INR ranged between 2 and 2.99 in 13.4% of patients, and INR values below 2 and above 5 were found in 44.2% and 21.2% of patients, respectively. Analgesics (n=54; 30.3%), cardiovascular drugs (n=51; 28.6%), and anticoagulants (n=46; 25.8%) were the most common drug classes that interact with warfarin. Significant and serious types of interactions with warfarin were found in 51% and 37.5% of patients, respectively.
CONCLUSION
This study highlights the complexity of managing warfarin therapy amid prevalent polypharmacy. A substantial majority of patients experienced multiple drug interactions. The identification of significant and serious interactions emphasizes the need for vigilant management strategies, including improved communication among healthcare professionals and targeted education for both providers and patients, to enhance the safety and efficacy of warfarin therapy.
PubMed: 38948431
DOI: 10.2147/IPRP.S458827 -
Asian Journal of Pharmaceutical Sciences Jun 2024Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites, increased therapeutic efficacy, and reduced adverse... (Review)
Review
Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites, increased therapeutic efficacy, and reduced adverse effects. Over the past few years, sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential. These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature. Inspired by their unique properties, thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine. In this review, the state-of-the-art developments in thermosensitive hydrogels for precision therapy are investigated, which covers from the thermo-gelling mechanisms and main components to biomedical applications, including wound healing, anti-tumor activity, osteogenesis, and periodontal, sinonasal and ophthalmic diseases. The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.
PubMed: 38948400
DOI: 10.1016/j.ajps.2024.100911 -
Reproductive Medicine and Biology 2024In an era of advanced maternal age, there is less conclusive evidence regarding the treatment outcomes of varicocele repair for assisted reproductive technology (ART).... (Review)
Review
BACKGROUNDS
In an era of advanced maternal age, there is less conclusive evidence regarding the treatment outcomes of varicocele repair for assisted reproductive technology (ART). Progress in basic research on varicocele is notable whereas there are many clinically relevant points to discuss.
METHODS
Based on our experience with more than 2000 cases of microsurgical varicocele repair, we focused on the effectiveness of varicocele repair, pathophysiology, surgical approaches, contributions to ART, sperm DNA fragmentation, and varicocele-associated azoospermia in this review with the aim of identifying clearer directions for basic and clinical research on varicocele.
RESULTS
Microsurgical low ligation for varicocele repair is expected to remain the gold standard for surgical therapy. Based on the findings from a number of systematic reviews and meta-analyses, negative opinions regarding the efficacy of microsurgical varicocele repair in male infertility treatment have become virtually nonexistent. However, the majority of evidence regarding surgical indications and effectiveness pertains to improvements in semen parameters or non-ART pregnancy rates.
CONCLUSIONS
Further understandings regarding to pathophysiology of varicocele will likely be gained through comprehensive genetic, transcriptomic, and epigenetic analyses using blood and testicular samples from humans and we hope to develop new diagnostic methods and pharmacotherapy.
PubMed: 38948338
DOI: 10.1002/rmb2.12589 -
Lancet Regional Health. Americas Jul 2024During COVID-19 in the US, social determinants of health (SDH) have driven health disparities. However, the use of SDH in COVID-19 vaccine modeling is unclear. This... (Review)
Review
UNLABELLED
During COVID-19 in the US, social determinants of health (SDH) have driven health disparities. However, the use of SDH in COVID-19 vaccine modeling is unclear. This review aimed to summarize the current landscape of incorporating SDH into COVID-19 vaccine transmission modeling in the US. Medline and Embase were searched up to October 2022. We included studies that used transmission modeling to assess the effects of COVID-19 vaccine strategies in the US. Studies' characteristics, factors incorporated into models, and approaches to incorporate these factors were extracted. Ninety-two studies were included. Of these, 11 studies incorporated SDH factors (alone or combined with demographic factors). Various sets of SDH factors were integrated, with occupation being the most common (8 studies), followed by geographical location (5 studies). The results show that few studies incorporate SDHs into their models, highlighting the need for research on SDH impact and approaches to incorporating SDH into modeling.
FUNDING
This research was funded by the Centers for Disease Control and Prevention (CDC).
PubMed: 38948323
DOI: 10.1016/j.lana.2024.100806