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Chembiochem : a European Journal of... Jun 2024Pain management following acute injury or post-operative procedures is highly necessary for proper recovery and quality of life. Opioids and non-steroidal...
Pain management following acute injury or post-operative procedures is highly necessary for proper recovery and quality of life. Opioids and non-steroidal anti-inflammatory drugs (NSAIDS) have been used for this purpose, but opioids cause addiction and withdrawal symptoms whereas NSAIDS have several systemic toxicities. Derivatives of the naturally occurring iboga alkaloids have previously shown promising behavior in anti-addiction of morphine by virtue of their interaction with opioid receptors. On this frontier, four benzofuran analogs of the iboga family have been synthesized and their analgesic effects have been studied in formalin induced acute pain model in Swiss albino mice at 30 mg/kg of body weight dose administered intraperitoneally. The antioxidant, anti-inflammatory and neuro-modulatory effects of the analogs were analyzed. Reversal of tail flick latency, restricted locomotion and anxiogenic behavior were observed in iboga alcohol, primary amide and secondary amide. Local neuroinflammatory mediators' substance P, calcitonin gene related peptide, cyclooxygenase-2 and p65 were significantly decreased whereas the depletion of brain derived neurotrophic factor and glia derived neurotrophic factor was overturned on iboga analog treatment. Behavioral patterns after oral administration of the best analog were also analyzed. Taken together, these results show that the iboga family of alkaloid has huge potential in pain management.
PubMed: 38874536
DOI: 10.1002/cbic.202400162 -
European Urology Oncology Jun 2024Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better...
BACKGROUND AND OBJECTIVE
Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC.
METHODS
We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure.
KEY FINDINGS AND CLINICAL IMPLICATIONS
We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles.
CONCLUSIONS AND CLINICAL IMPLICATIONS
Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism.
PATIENT SUMMARY
We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.
PubMed: 38862340
DOI: 10.1016/j.euo.2024.05.011 -
BioRxiv : the Preprint Server For... May 2024Genetic factors and microbial imbalances play crucial roles in colorectal cancers (CRCs), yet the impact of infections on cancer initiation remains poorly understood....
BACKGROUND
Genetic factors and microbial imbalances play crucial roles in colorectal cancers (CRCs), yet the impact of infections on cancer initiation remains poorly understood. While bioinformatic approaches offer valuable insights, the rising incidence of CRCs creates a pressing need to precisely identify early CRC events. We constructed a network model to identify continuum states during CRC initiation spanning normal colonic tissue to pre-cancer lesions (adenomatous polyps) and examined the influence of microbes and host genetics.
METHODS
A Boolean network was built using a publicly available transcriptomic dataset from healthy and adenoma affected patients to identify an invariant Microbe-Associated Colorectal Cancer Signature (MACS). We focused on ( ), a CRC-associated microbe, as a model bacterium. MACS-associated genes and proteins were validated by RT-qPCR, RNA seq, ELISA, IF and IHCs in tissues and colon-derived organoids from genetically predisposed mice ( ) and patients (FAP, Lynch Syndrome, PJS, and JPS).
RESULTS
The MACS that is upregulated in adenomas consists of four core genes/proteins: CLDN2/Claudin-2 (leakiness), LGR5/leucine-rich repeat-containing receptor (stemness), CEMIP/cell migration-inducing and hyaluronan-binding protein (epithelial-mesenchymal transition) and IL8/Interleukin-8 (inflammation). MACS was induced upon infection, but not in response to infection with other enteric bacteria or probiotics. MACS induction upon infection was higher in organoids compared to WT controls. The degree of MACS expression in the patient-derived organoids (PDOs) generally corresponded with the known lifetime risk of CRCs.
CONCLUSIONS
Computational prediction followed by validation in the organoid-based disease model identified the early events in CRC initiation. MACS reveals that the CRC-associated microbes induce a greater risk in the genetically predisposed hosts, suggesting its potential use for risk prediction and targeted cancer prevention.
PubMed: 38853996
DOI: 10.1101/2024.05.26.595902 -
Brain, Behavior, and Immunity Jun 2024Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk...
Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk factors for social anxiety exist, it is currently unknown how social fear sensitivity manifests biologically. Furthermore, since some individuals are resilient and others are susceptible to social fear, it is important to interrogate the mechanisms underpinning individual response to social fear situations. The microbiota-gut-brain axis has been associated with social behaviour, has recently been linked with social anxiety disorder, and may serve as a therapeutic target for modulation. Here, we assess the potential of this axis to be linked with social fear extinction processes in a murine model of social anxiety disorder. To this end, we correlated differential social fear responses with microbiota composition, central gene expression, and immune responses. Our data provide evidence that microbiota variability is strongly correlated with alterations in social fear behaviour. Moreover, we identified altered gene candidates by amygdalar transcriptomics that are linked with social fear sensitivity. These include genes associated with social behaviour (Armcx1, Fam69b, Kcnj9, Maoa, Serinc5, Slc6a17, Spata2, and Syngr1), inflammation and immunity (Cars, Ckmt1, Klf5, Maoa, Map3k12, Pex5, Serinc5, Sidt1, Spata2), and microbe-host interaction (Klf5, Map3k12, Serinc5, Sidt1). Together, these data provide further evidence for a role of the microbiota-gut-brain axis in social fear responses.
PubMed: 38852762
DOI: 10.1016/j.bbi.2024.06.009 -
Toxicological Sciences : An Official... Jun 2024Lorcaserin is a 5-hydroxytryptamine 2C (serotonin) receptor agonist and a non-genotoxic rat carcinogen, which induced mammary tumors in male and female rats in a...
Lorcaserin is a 5-hydroxytryptamine 2C (serotonin) receptor agonist and a non-genotoxic rat carcinogen, which induced mammary tumors in male and female rats in a two-year bioassay. Female Sprague Dawley rats were treated by gavage daily with 0, 30, or 100 mg/kg lorcaserin, replicating bioassay dosing but for shorter duration, 12 or 24 weeks. To characterize exposure and eliminate possible confounding by a potentially genotoxic degradation product, lorcaserin and N-nitroso-lorcaserin were quantified in dosing solutions, terminal plasma, mammary and liver samples using ultra high-performance liquid chromatography-electrospray tandem mass spectrometry. N-nitroso-lorcaserin was not detected, supporting lorcaserin classification as non-genotoxic carcinogen. Mammary DNA samples (n = 6/dose/timepoint) were used to synthesize PCR products from gene segments encompassing hotspot cancer driver mutations (CDMs), namely regions of Apc, Braf, Egfr, Hras, Kras, Nfe2l2, Pik3ca, Setbp1, Stk11, and Tp53. Mutant fractions (MFs) in the amplicons were quantified by CarcSeq, an error corrected next-generation sequencing approach. Considering all recovered mutants, no significant differences between lorcaserin dose groups were observed. However, significant dose-responsive increases in Pik3ca H1047R mutation were observed at both timepoints (ANOVA, p < 0.05), with greater numbers of mutants and mutants with greater MFs observed at 24 weeks as compared to 12 weeks. These observations suggest lorcaserin promotes outgrowth of spontaneously occurring Pik3ca H1047R mutant clones leading to mammary carcinogenesis. Importantly, this work reports approaches to analyze clonal expansion and demonstrates CarcSeq detection of the carcinogenic impact (selective Pik3ca H0147R mutant expansion) of a non-genotoxic carcinogen using a treatment duration as short as 3 months.
PubMed: 38851877
DOI: 10.1093/toxsci/kfae070 -
Cell May 2024Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs)...
Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs) within the global microbiome and leverage a vast dataset of 63,410 metagenomes and 87,920 prokaryotic genomes from environmental and host-associated habitats to create the AMPSphere, a comprehensive catalog comprising 863,498 non-redundant peptides, few of which match existing databases. AMPSphere provides insights into the evolutionary origins of peptides, including by duplication or gene truncation of longer sequences, and we observed that AMP production varies by habitat. To validate our predictions, we synthesized and tested 100 AMPs against clinically relevant drug-resistant pathogens and human gut commensals both in vitro and in vivo. A total of 79 peptides were active, with 63 targeting pathogens. These active AMPs exhibited antibacterial activity by disrupting bacterial membranes. In conclusion, our approach identified nearly one million prokaryotic AMP sequences, an open-access resource for antibiotic discovery.
PubMed: 38843834
DOI: 10.1016/j.cell.2024.05.013 -
JCO Global Oncology Jun 2024In high-income countries, 2%-10% of tumor genomic profiling (TGP) reports reveal incidental pathogenic germline variants. A third of these patients would not qualify for...
PURPOSE
In high-income countries, 2%-10% of tumor genomic profiling (TGP) reports reveal incidental pathogenic germline variants. A third of these patients would not qualify for genetic testing on the basis of current guidelines. Our study determined the prevalence of potentially pathogenic germline variants (PPGVs) in TGP results of adult patients with solid malignancies in the Philippines.
METHODS
Annotated reports of patients with solid cancers who underwent TGP using FoundationOne or FoundationOne Heme between January 2021 and July 2023 were reviewed. PPGV criteria include having a variant allele frequency of >30% and were categorized as (1) high penetrance gene (HP), founder variant (FV), or variant associated with clinical presentation (VA). Pathogenicity was crosschecked through the ClinVar database.
RESULTS
Of 446 patients, 13 PPGV variants were found in 50 (11.2%) patients at a median age of 60.5 years. Of them, 28 (56%) had HP (, , , , , , ), 25 (50%) patients had VA (, , , , ), and two patients with lung cancer had a FV ( p.Thr790Met). Six patients had more than one PPGV. PPGVs were primarily found in patients with colorectal (42% of 50 patients with PPGVs), breast (16%), ovarian (6%), and lung (6%) cancer ( < .001). HP genes were mostly found in female patients (71.4%; = .03).
CONCLUSION
With a PPGV prevalence of 11% in this study, it is important to recognize PPGVs as it can prompt genetic counseling and confirmatory germline testing.
Topics: Humans; Female; Male; Philippines; Middle Aged; Germ-Line Mutation; Neoplasms; Aged; Adult; Prevalence; Genetic Predisposition to Disease; Genetic Testing; Aged, 80 and over; Genomics
PubMed: 38843470
DOI: 10.1200/GO.24.00019 -
Science (New York, N.Y.) Jun 2024How the oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase...
How the oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Transcriptome; HEK293 Cells
PubMed: 38843331
DOI: 10.1126/science.adk0775 -
Microbiome Research Reports 2024subsp. is a dominant bacterium in infant gut, which plays a critical role in maintaining the health and development of infants. This study investigated the abilities...
subsp. is a dominant bacterium in infant gut, which plays a critical role in maintaining the health and development of infants. This study investigated the abilities of eight different strains of subsp. to regulate the T helper (Th)1/Th2 balance. Eight . subsp. strains, including I2MI (FJSWXI2MIM1), I4MI [FJSWXI4MI (CCFM1270)], I4MNI (FJSWXI4MNIM1), I5TI (FJSWXI5TIM1), I6TI (FJSWXI6TIM1), I8TI [FJSWXI8TI (CCFM1271)], I10TI [FJSWXI10TI (CCFM1272)], and B6MNI [BJSWXB6MNIM1 (CCFM1269)], were gavaged to BALB/C pups in both female ( = 8) and male ( = 8) mice starting from 1 to 3 weeks old (1 × 10 CFU/day/mice). Selected immune cells were assessed by immunofluorescence and flow cytometry. Cytokines and immunoglobulins were determined by ELISA. Bacterial and bifidobacterial communities were determined by gene sequencing and bifidobacterial sequencing. . subsp. I4MI and I8TI were shown to increase the ration of colonic IgG2a/IgE in male mice ( < 0.05). B6MNI was demonstrated to significantly increase the levels of colonic IFN-γ and IgG2a, as well as the ratio of IgG2a/IgE in female mice ( < 0.05). It was also shown to significantly increase the ratio of colonic IgG2a/IgE ( < 0.05) and reduce the level of colonic IL-4 in male mice ( < 0.05). Furthermore, B6MNI was demonstrated to regulate colonic JAK/STAT pathway in both male and female mice. I4MI, I5TI, and B6MNI were shown to increase the relative abundance of and subsp. in both male and female mice, whereas I8TI was only shown to increase the relative abundance of and subsp. in male mice ( < 0.05). These results indicated supplementation with subsp. in early infancy may regulate the Th1/Th2 immune balance, which may prevent the development of related diseases.
PubMed: 38841405
DOI: 10.20517/mrr.2023.64 -
Computers in Biology and Medicine Jul 2024G-Quadruplex DNA (GQ-DNA) is one of the most important non-canonical nucleic acid structures. GQ-DNA forming sequences are present in different crucial genomic regions...
Investigating the preferential interaction between imatinib mesylate and VEGF G-quadruplex DNA as therapeutic strategies for cancer treatment: Biophysical and molecular modelling approaches.
G-Quadruplex DNA (GQ-DNA) is one of the most important non-canonical nucleic acid structures. GQ-DNA forming sequences are present in different crucial genomic regions and are abundant in promoter regions of several oncogenes. Therefore, GQ-DNA is an important target for anticancer drugs and hence binding interactions between GQ-DNA and small molecule ligands are of great importance. Since GQ-DNA is a highly polymorphic structure, it is important to identify ligand molecules which preferentially target a particular quadruplex sequence. In this present study, we have used a FDA approved drug called imatinib mesylate (ligand) which is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia, gastrointestinal stromal tumours. Different spectroscopic techniques as well as molecular docking investigations and molecular simulations have been used to explore the interaction between imatinib mesylate with VEGF GQ DNA structures along with duplex DNA, C-Myc, H-Telo GQ DNA. We found that imatinib mesylate shows preferential interaction towards VEGF GQ DNA compared to C-Myc, H-Telo GQ and duplex DNA. Imatinib mesylate seems to be an efficient ligand for VEGF GQ DNA, suggesting that it might be used to regulate the expression of genes in cancerous cells.
Topics: Imatinib Mesylate; G-Quadruplexes; Humans; Vascular Endothelial Growth Factor A; Molecular Docking Simulation; Antineoplastic Agents; Neoplasms; DNA
PubMed: 38838555
DOI: 10.1016/j.compbiomed.2024.108683