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Haematologica Nov 2023Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic...
Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options.
PubMed: 37981895
DOI: 10.3324/haematol.2023.283917 -
Cellular and Molecular Life Sciences :... Nov 2023Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately...
BACKGROUND
Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately 30% of those glutamatergic inputs come from thalamic nuclei. Foxp2 is a transcription factor involved in cell differentiation and reported low in patients with HD. However, the role of the Foxp2 in the thalamus in HD remains unexplored.
METHODS
We used two different mouse models of HD, the R6/1 and the HdhQ111 mice, to demonstrate a consistent thalamic Foxp2 reduction in the context of HD. We used in vivo electrophysiological recordings, microdialysis in behaving mice and rabies virus-based monosynaptic tracing to study thalamo-striatal and thalamo-cortical synaptic connectivity in R6/1 mice. Micro-structural synaptic plasticity was also evaluated in the striatum and cortex of R6/1 mice. We over-expressed Foxp2 in the thalamus of R6/1 mice or reduced Foxp2 in the thalamus of wild type mice to evaluate its role in sensory and motor skills deficiencies, as well as thalamo-striatal and thalamo-cortical connectivity in such mouse models.
RESULTS
Here, we demonstrate in a HD mouse model a clear and early thalamo-striatal aberrant connectivity associated with a reduction of thalamic Foxp2 levels. Recovering thalamic Foxp2 levels in the mouse rescued motor coordination and sensory skills concomitant with an amelioration of neuropathological features and with a repair of the structural and functional connectivity through a restoration of neurotransmitter release. In addition, reduction of thalamic Foxp2 levels in wild type mice induced HD-like phenotypes.
CONCLUSIONS
In conclusion, we show that a novel identified thalamic Foxp2 dysregulation alters basal ganglia circuits implicated in the pathophysiology of HD.
Topics: Humans; Animals; Mice; Huntington Disease; Motor Disorders; Thalamus; Corpus Striatum; Movement; Disease Models, Animal; Repressor Proteins; Forkhead Transcription Factors
PubMed: 37987826
DOI: 10.1007/s00018-023-05015-z -
PLoS Biology Oct 2023Arthropod-borne pathogens cause some of the most important human and animal infectious diseases. Many vectors acquire or transmit pathogens through the process of blood...
Arthropod-borne pathogens cause some of the most important human and animal infectious diseases. Many vectors acquire or transmit pathogens through the process of blood feeding. Here, we report adiponectin, the most abundant adipocyte-derived hormone circulating in human blood, directly or indirectly inhibits acquisition of the Lyme disease agent, Borrelia burgdorferi, by Ixodes scapularis ticks. Rather than altering tick feeding or spirochete viability, adiponectin or its associated factors induces host histamine release when the tick feeds, which leads to vascular leakage, infiltration of neutrophils and macrophages, and inflammation at the bite site. Consistent with this, adiponectin-deficient mice have diminished pro-inflammatory responses, including interleukin (IL)-12 and IL-1β, following a tick bite, compared with wild-type animals. All these factors mediated by adiponectin or associated factors influence B. burgdorferi survival at the tick bite site. These results suggest a host adipocyte-derived hormone modulates pathogen acquisition by a blood-feeding arthropod.
Topics: Animals; Mice; Humans; Adiponectin; Tick Bites; Borrelia burgdorferi Group; Lyme Disease; Ixodes; Mammals
PubMed: 37862360
DOI: 10.1371/journal.pbio.3002331 -
The Journal of Neuroscience : the... Nov 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Recently, genome-wide association studies identified KIF5A as a new...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Recently, genome-wide association studies identified KIF5A as a new ALS-causing gene. KIF5A encodes a protein of the kinesin-1 family, allowing the anterograde transport of cargos along the microtubule rails in neurons. In ALS patients, mutations in the KIF5A gene induce exon 27 skipping, resulting in a mutated protein with a new C-terminal region (KIF5A Δ27). To understand how KIF5A Δ27 underpins the disease, we developed an ALS-associated KIF5A model. When selectively expressed in motor neurons, KIF5A Δ27 alters larval locomotion as well as morphology and synaptic transmission at neuromuscular junctions in both males and females. We show that the distribution of mitochondria and synaptic vesicles is profoundly disturbed by KIF5A Δ27 expression. That is consistent with the numerous KIF5A Δ27-containing inclusions observed in motor neuron soma and axons. Moreover, KIF5A Δ27 expression leads to motor neuron death and reduces life expectancy. Our model reveals that a toxic gain of function underlies the pathogenicity of ALS-linked KIF5A mutant. Understanding how a mutation identified in patients with amyotrophic lateral sclerosis (ALS) causes the disease and the loss of motor neurons is crucial to fight against this disease. To this end, we have created a model based on the motor neuron expression of the KIF5A mutant gene, recently identified in ALS patients. KIF5A encodes a kinesin that allows the anterograde transport of cargos. This model recapitulates the main features of ALS, including alterations of locomotion, synaptic neurotransmission, and morphology at neuromuscular junctions, as well as motor neuron death. KIF5A mutant is found in cytoplasmic inclusions, and its pathogenicity is because of a toxic gain of function.
Topics: Male; Animals; Female; Humans; Amyotrophic Lateral Sclerosis; Kinesins; Genome-Wide Association Study; Neurodegenerative Diseases; Motor Neurons; Neuromuscular Junction; Mutation; Drosophila; Inclusion Bodies
PubMed: 37748861
DOI: 10.1523/JNEUROSCI.0562-23.2023 -
World Journal of Clinical Cases May 2024Despite the increasing scientific interest and expanding role of gut microbiota (GM) in human health, it is rarely reported in case reports and deployed in clinical...
Despite the increasing scientific interest and expanding role of gut microbiota (GM) in human health, it is rarely reported in case reports and deployed in clinical practice. Proteins and metabolites produced by microbiota contribute to immune system development, energy homeostasis and digestion. Exo- and endogenous factors can alter its composition. Disturbance of microbiota, also known as dysbiosis, is associated with various pathological conditions. Specific bacterial taxa and related metabolites are involved in disease pathogenesis and therefore can serve as a diagnostic tool. GM could also be a useful prognostic factor by predicting future disease onset and preventing hospital-associated infections. Additionally, it can influence response to treatments, including those for cancers, by altering drug bioavailability. A thorough understanding of its function has permitted significant development in therapeutics, such as probiotics and fecal transplantation. Hence, GM should be considered as a ground-breaking biological parameter, and it is advisable to be investigated and reported in literature in a more consistent and systematic way.
PubMed: 38765739
DOI: 10.12998/wjcc.v12.i14.2293 -
Frontiers in Cellular Neuroscience 2023Normal brain development, function, and aging critically depend on unique characteristics of the cerebrovascular system. Growing evidence indicated that cerebrovascular... (Review)
Review
Normal brain development, function, and aging critically depend on unique characteristics of the cerebrovascular system. Growing evidence indicated that cerebrovascular defects can have irreversible effects on the brain, and these defects have been implicated in various neurological disorders, including autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder with heterogeneous clinical manifestations and anatomical changes. While extensive research has focused on the neural abnormalities underlying ASD, the role of brain vasculature in this disorder remains poorly understood. Indeed, the significance of cerebrovascular contributions to ASD has been consistently underestimated. In this work, we discuss the neurovascular crosstalk during embryonic development and highlight recent findings on cerebrovascular alterations in individuals with ASD. We also discuss the potential of vascular-based therapy for ASD. Collectively, these investigations demonstrate that ASD can be considered a neurovascular disease.
PubMed: 37692552
DOI: 10.3389/fncel.2023.1226580 -
Reproductive Biology and Endocrinology... Jan 2024Increasing number of studies have demonstrated certain patterns of microbial changes in gynecological diseases; however, the interaction between them remains unclear. To... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Increasing number of studies have demonstrated certain patterns of microbial changes in gynecological diseases; however, the interaction between them remains unclear. To evaluate the consistency or specificity across multiple studies on different gynecological diseases and microbial alterations at different sites of the body (gut and genital tract), we conducted a systematic review and meta-analysis.
METHODS
We searched PubMed, Embase, Web of Science, and Cochrane Library up to December 5, 2022(PROSPERO: CRD42023400205). Eligible studies focused on gynecological diseases in adult women, applied next-generation sequencing on microbiome, and reported outcomes including alpha or beta diversity or relative abundance. The random-effects model on standardized mean difference (SMD) was conducted using the inverse-variance method for alpha diversity indices.
RESULTS
Of 3327 unique articles, 87 eligible studies were included. Significant decreases were found in gut microbiome of patients versus controls (observed species SMD=-0.35; 95%CI, -0.62 to -0.09; Shannon index SMD=-0.23; 95%CI, -0.40 to -0.06), whereas significant increases were observed in vaginal microbiome (Chao1 SMD = 1.15; 95%CI, 0.74 to 1.56; Shannon index SMD = 0.51; 95%CI, 0.16 to 0.86). Most studies of different diagnostic categories showed no significant differences in beta diversity. Disease specificity was observed, but almost all the changes were only replicated in three studies, except for the increased Aerococcus in bacterial vaginosis (BV). Patients with major gynecological diseases shared the enrichment of Prevotella and depletion of Lactobacillus, and an overlap in microbes was implied between BV, cervical intraepithelial neoplasia, and cervical cancer.
CONCLUSIONS
These findings demonstrated an association between alterations in gut and genital microbiota and gynecological diseases. The most observed results were shared alterations across diseases rather than disease-specific alterations. Therefore, further investigation is required to identify specific biomarkers for diagnosis and treatment in the future.
Topics: Adult; Humans; Female; Microbiota; Vaginosis, Bacterial; Gastrointestinal Microbiome; Vagina; Uterine Cervical Neoplasms
PubMed: 38238814
DOI: 10.1186/s12958-024-01184-z -
Cell Calcium Sep 2023Inositol 1,4,5-trisphosphate receptors (IPRs) are ER Ca-release channels that control a broad set of cellular processes. Animal models lacking IPRs in different...
Inositol 1,4,5-trisphosphate receptors (IPRs) are ER Ca-release channels that control a broad set of cellular processes. Animal models lacking IPRs in different combinations display severe developmental phenotypes. Given the importance of IPRs in human diseases, we investigated their role in human induced pluripotent stem cells (hiPSC) by developing single IPR and triple IPR knockouts (TKO). Genome edited TKO-hiPSC lacking all three IPR isoforms, IPR1, IPR2, IPR3, failed to generate Ca signals in response to agonists activating GPCRs, but retained stemness and pluripotency. Steady state metabolite profiling and flux analysis of TKO-hiPSC indicated distinct alterations in tricarboxylic acid cycle metabolites consistent with a deficiency in their pyruvate utilization via pyruvate dehydrogenase, shifting towards pyruvate carboxylase pathway. These results demonstrate that IPRs are not essential for hiPSC identity and pluripotency but regulate mitochondrial metabolism. This set of knockout hiPSC is a valuable resource for investigating IPRs in human cell types of interest.
PubMed: 37481871
DOI: 10.1016/j.ceca.2023.102782 -
Gland Surgery Sep 2023Autologous breast reconstruction has consistently demonstrated excellent patient satisfaction, ideal aesthetic results, and a low risk of complications. With the... (Review)
Review
Autologous breast reconstruction has consistently demonstrated excellent patient satisfaction, ideal aesthetic results, and a low risk of complications. With the increasing incidence of breast cancer diagnoses and higher reconstruction rates, surgeons encounter a broader spectrum of patients. Obese patients undergoing breast reconstruction are more likely to experience a surgical complication. While free tissue transfer carries a higher donor site complication rate, implant-based reconstruction carries a higher loss of reconstruction in this population. Additionally, autologous reconstruction consistently demonstrates better patient-reported outcomes. Oncoplastic reconstruction is an oncologically safe alternative to free tissue transfer and implant reconstruction which reduces the risk of complications and the risk of delaying adjuvant therapy. Particularly in obese patients for whom radiation is indicated based on tumor size or nodal involvement, oncoplastic reconstruction is maximally beneficial. The Goldilocks mastectomy is yet another alternative to free tissue transfer or implant reconstruction which carries an acceptable risk profile, especially when augmentation with tissue expander or implant is delayed and performed at a second stage. In patients with breast ptosis undergoing skin-sparing mastectomy, vertical skin reduction allows an acceptable aesthetic result while minimizing the risk for mastectomy flap necrosis (MFN), especially in comparison to Wise pattern skin reduction. If a nipple-sparing mastectomy (NSM) is to be performed in the setting of breast ptosis, a nipple delay or a pre-mastectomy reduction/mastopexy is the safest and most conservative approach, but can alter the timeline for primary cancer resection and therefore is predominantly performed in patients with a genetic predisposition or those undergoing a prophylactic mastectomy. Patients with obesity, breast ptosis, advanced age, active smoking history, prior radiation therapy, or abdominal procedures can carry an increased risk of complications and present a challenge to plastic surgeons. We review the most recent literature published regarding reconstruction in these patient groups and seek to provide practical information to help inform clinical decision-making and operative execution.
PubMed: 37842527
DOI: 10.21037/gs-22-710 -
Archives of Pathology & Laboratory... Dec 2023Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized.
CONTEXT.—
Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized.
OBJECTIVE.—
To investigate their morphologic, immunohistochemical, and molecular features.
DESIGN.—
Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing.
RESULTS.—
The mean age at diagnosis was 69 years (42-81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%).
CONCLUSIONS.—
Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.
Topics: Humans; Male; Female; Aged; Bile Ducts; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Carcinoma, Papillary; Bile Duct Neoplasms
PubMed: 36821179
DOI: 10.5858/arpa.2022-0343-OA