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Biology Apr 2024Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is... (Review)
Review
Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is established that metformin reduces mitochondrial respiration, but its specific molecular targets within mitochondria vary. Proposed mechanisms include inhibiting mitochondrial respiratory chain Complex I and/or Complex IV, and mitochondrial glycerophosphate dehydrogenase, among others. These actions lead to cellular energy deficits, redox state changes, and several molecular changes that reduce hyperglycemia in type 2 diabetic patients. Clinical evidence supports metformin's role in cancer prevention in type 2 diabetes mellitus patients. Moreover, in these patients with breast and colorectal cancer, metformin consumption leads to an improvement in survival outcomes and prognosis. The synergistic effects of metformin with chemotherapy and immunotherapy highlights its potential as an adjunctive therapy for breast and colorectal cancer. However, nuanced findings underscore the need for further research and stratification by molecular subtype, particularly for breast cancer. This comprehensive review integrates metformin-related findings from epidemiological, clinical, and preclinical studies in breast and colorectal cancer. Here, we discuss current research addressed to define metformin's bioavailability and efficacy, exploring novel metformin-based compounds and drug delivery systems, including derivatives targeting mitochondria, combination therapies, and novel nanoformulations, showing enhanced anticancer effects.
PubMed: 38785784
DOI: 10.3390/biology13050302 -
Brain Communications 2024Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's...
Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, C-labelled Pittsburgh Compound B-PET and structural MRI. F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB cerebellar grey reference and FDG pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, = 0.96) and greater global cortical F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.
PubMed: 38784820
DOI: 10.1093/braincomms/fcae159 -
Ethiopian Journal of Health Sciences Jul 2023Diffusion-weighted imaging (DWI) is the random Brownian motion of water molecules within a tissue voxel. The apparent diffusion coefficient (ADC) is a quantitative... (Observational Study)
Observational Study Comparative Study
BACKGROUND
Diffusion-weighted imaging (DWI) is the random Brownian motion of water molecules within a tissue voxel. The apparent diffusion coefficient (ADC) is a quantitative parameter calculated from the DWI that directly reflects the mobility of water molecules in biological tissues. The objective of this study was to establish and compare the normal reference ADC values of fetal organs and the placenta using 1.5 T and 3.0 T MRI at various gestational ages.
METHODS
This was a retrospective and prospective observational study. This study included one hundred and three (103) singleton pregnancies for each magnetic field strength. Diffusion-weighted imaging was performed using single-shot spin-echo-planar imaging (EPI) in the axial plane of the fetal head-trunk with a slice thickness of 4mm and diffusion gradient values of b = 0 and b = 700-800 s/mm.
RESULTS
The mean ADC values of cerebral WM areas were significantly higher than the deep grey areas in the brain. The white-matter regions, lung, and placenta showed a positive and significant correlation with increasing gestational age in both field strengths. A statistically weak negative correlation was observed between increasing gestational age and ADC measurements obtained in the thalamus, cerebellum, pons, and kidney.
CONCLUSION
This study gives the reference values for both 1.5T and 3T MRI of vital organs. The current study shows that diffusion-weighted MRI can offer a promising technique to evaluate the structural development of fetal organs and can potentially act as a biomarker for predicting the functionality of the fetal organs in abnormalities.
Topics: Humans; Female; Pregnancy; Placenta; Gestational Age; Adult; Diffusion Magnetic Resonance Imaging; Prospective Studies; Retrospective Studies; Fetus; Reference Values; Brain; Young Adult; Echo-Planar Imaging
PubMed: 38784210
DOI: 10.4314/ejhs.v33i4.8 -
Nucleic Acids Research Jul 2024Among the myriad of protein-protein interactions occurring in living organisms, a substantial amount involves small linear motifs (SLiMs) recognized by structured...
Among the myriad of protein-protein interactions occurring in living organisms, a substantial amount involves small linear motifs (SLiMs) recognized by structured domains. However, predictions of SLiM-based networks are tedious, due to the abundance of such motifs and a high portion of false positive hits. For this reason, a webserver SLiMAn (Short Linear Motif Analysis) was developed to focus the search on the most relevant SLiMs. Using SLiMAn, one can navigate into a given (meta-)interactome and tune a variety of parameters associated to each type of SLiMs in attempt to identify functional ELM motifs and their recognition domains. The IntAct and BioGRID databases bring experimental information, while IUPred and AlphaFold provide boundaries of folded and disordered regions. Post-translational modifications listed in PhosphoSite+ are highlighted. Links to PubMed accelerate scrutiny into the literature, to support (or not) putative pairings. Dedicated visualization features are also incorporated, such as Cytoscape for macromolecular networks and BINANA for intermolecular contacts within structural models generated by SCWRL 3.0. The use of SLiMAn 2.0 is illustrated on a simple example. It is freely available at https://sliman2.cbs.cnrs.fr.
Topics: Peptides; Software; Protein Interaction Mapping; Protein Interaction Maps; Databases, Protein; Humans; Amino Acid Motifs; Proteins; Internet; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational
PubMed: 38783158
DOI: 10.1093/nar/gkae398 -
Nature Jun 2024Chiral molecules, used in applications such as enantioselective photocatalysis, circularly polarized light detection and emission and molecular switches, exist in two...
Chiral molecules, used in applications such as enantioselective photocatalysis, circularly polarized light detection and emission and molecular switches, exist in two geometrical configurations that are non-superimposable mirror images of each other. These so-called (R) and (S) enantiomers exhibit different physical and chemical properties when interacting with other chiral entities. Attosecond technology might enable influence over such interactions, given that it can probe and even direct electron motion within molecules on the intrinsic electronic timescale and thereby control reactivity. Electron currents in photoexcited chiral molecules have indeed been predicted to enable enantiosensitive molecular orientation, but electron-driven chiral dynamics in neutral molecules have not yet been demonstrated owing to the lack of ultrashort, non-ionizing and perturbative light pulses. Here we use time-resolved photoelectron circular dichroism (TR-PECD) with an unprecedented temporal resolution of 2.9 fs to map the coherent electronic motion initiated by ultraviolet (UV) excitation of neutral chiral molecules. We find that electronic beatings between Rydberg states lead to periodic modulations of the chiroptical response on the few-femtosecond timescale, showing a sign inversion in less than 10 fs. Calculations validate this and also confirm that the combination of the photoinduced chiral current with a circularly polarized probe pulse realizes an enantioselective filter of molecular orientations following photoionization. We anticipate that our approach will enable further investigations of ultrafast electron dynamics in chiral systems and reveal a route towards enantiosensitive charge-directed reactivity.
PubMed: 38778116
DOI: 10.1038/s41586-024-07415-y -
The Science of the Total Environment Sep 2024Free-living amoebae (FLA) such as Acanthamoeba, Balamuthia mandrillaris, Naegleria fowleri and Sappinia pedata are naturally widespread in freshwater, causing rare but...
Free-living amoebae (FLA) such as Acanthamoeba, Balamuthia mandrillaris, Naegleria fowleri and Sappinia pedata are naturally widespread in freshwater, causing rare but fatal and debilitating infections in humans. Although recent studies have shown an increase in infection rates, there is a paucity of epidemiological studies regarding the presence of these emerging pathogens in water. Herein, we studied the diversity and relative abundance of thermophilic FLA in different recreational baths in a tropical climate for 5 years. From 2018 to 2022, a total of 96 water samples were collected from 7 recreational baths (natural, tiled, regularly cleaned or not, and with temperatures ranging from 27 to 40 °C). DNA was extracted from FLA cultivated at 37 °C to detect thermophilic culturable FLA. Metabarcoding studies were conducted through FLA 18S rRNA gene amplicons sequencing; amplicon sequence variants (ASV) were extracted from each sample and taxonomy assigned against PR2 database using dada2 and phyloseq tools. We also searched for Naegleria sp. and N. fowleri using PCR targeting ITS and NFITS genes (respectively) and we quantified them using an optimized most probable number (MPN) method for FLA. Our results showed that differences in FLA diversity and abundance were observed amongst the 7 baths, but without a clear seasonal distribution. Naegleria, Vermamoeba and Stenamoeba were the most represented genera, while the genera Acanthamoeba and Vahlkampfia were mainly found in 2 baths. The MPN values for Naegleria sp. (NT/l) increased between 2018 and 2022, but the MPN values for N. fowleri (NF/l) seemed to decrease. Globally, our results showed that since we cannot establish a seasonal distribution of FLA, the regular presence of FLA (namely Naegleria and Acanthamoeba) in recreational waters can pose a potential threat in terms of neuroinfections as well as Acanthamoeba keratitis. It is thus imperious to perform the regular control of these baths as a preventive health measure.
Topics: Amoeba; Guadeloupe; Environmental Monitoring; Fresh Water; Bathing Beaches
PubMed: 38777057
DOI: 10.1016/j.scitotenv.2024.173318 -
Frontiers in Genetics 2024Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The... (Review)
Review
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The median age at diagnosis is 6-7 years old, with less than 10% overall survival 2 years after diagnosis and less than 1% after 5 years. DIPGs are surgically inaccessible, and radiation therapy provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children, with a societal cancer burden in years of life lost (YLL) of more than 67 per individual, approximately 14 and 16 YLL for lung and breast cancer respectively. More than 95 clinical drug trials have been conducted on children with DIPGs, and all have failed to improve survival. No single or combination chemotherapeutic strategy has been successful to date because of our inability to identify targeted drugs for this disease and to deliver these drugs across an intact blood-brain barrier (BBB). Accordingly, there has been an increased focus on immunotherapy research in DIPG, with explorations into treatments such as chimeric antigen receptor T (CAR-T) cells, immune checkpoint blockades, cancer vaccines, and autologous cell transfer therapy. Here, we review the most recent advances in identifying genetic factors influencing the development of immunotherapy for DIPG. Additionally, we explore emerging technologies such as Magnetic Resonance-guided Focused Ultrasound (MRgFUS) in potential combinatorial approaches to treat DIPG.
PubMed: 38774284
DOI: 10.3389/fgene.2024.1349612 -
Current Biology : CB Jun 2024ON and OFF thalamic afferents from the two eyes converge in the primary visual cortex to form binocular receptive fields. The receptive fields need to be diverse to...
ON and OFF thalamic afferents from the two eyes converge in the primary visual cortex to form binocular receptive fields. The receptive fields need to be diverse to sample our visual world but also similar across eyes to achieve binocular fusion. It is currently unknown how the cortex balances these competing needs between receptive-field diversity and similarity. Our results demonstrate that receptive fields in the cat visual cortex are binocularly matched with exquisite precision for retinotopy, orientation/direction preference, orientation/direction selectivity, response latency, and ON-OFF polarity/structure. Specifically, the average binocular mismatches in retinotopy and ON-OFF structure are tightly restricted to 1/20 and 1/5 of the average receptive-field size but are still large enough to generate all types of binocular disparity tuning. Based on these results, we conclude that cortical receptive fields are binocularly matched with the high precision needed to facilitate binocular fusion while allowing restricted mismatches to process visual depth.
Topics: Animals; Cats; Vision, Binocular; Primary Visual Cortex; Visual Fields; Visual Cortex; Vision Disparity
PubMed: 38772362
DOI: 10.1016/j.cub.2024.04.058 -
Neurology Jun 2024
Topics: Humans; Synkinesis; Pons; Male; Demyelinating Diseases; Magnetic Resonance Imaging; Female; Abducens Nerve Diseases; Middle Aged
PubMed: 38771991
DOI: 10.1212/WNL.0000000000209542 -
Proceedings of the National Academy of... May 2024Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine...
Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine projections. We predicted that an exploitation-bias that emerges in older adulthood would be associated with lower microstructural integrity of the locus coeruleus. Leveraging in vivo histological methods from quantitative MRI-magnetic transfer saturation-we provide evidence that older age is associated with lower locus coeruleus integrity. Critically, we demonstrate that an exploitation bias in older adulthood, assessed with a foraging task, is sensitive and specific to lower locus coeruleus integrity. Because the locus coeruleus is uniquely vulnerable to Alzheimer's disease pathology, our findings suggest that aging, and a presymptomatic trajectory of Alzheimer's related decline, may fundamentally alter decision-making abilities in later life.
Topics: Locus Coeruleus; Humans; Decision Making; Aged; Male; Female; Aging; Magnetic Resonance Imaging; Alzheimer Disease; Middle Aged; Aged, 80 and over; Reward
PubMed: 38771873
DOI: 10.1073/pnas.2322617121