Demographic profile and outcome in primary pediatric brain tumors. A single tertiary institute experience in India

Introduction: Pediatric brain tumors are the most common tumor in children after hematological malignancies. There is very few data about the epidemiology of pediatric brain tumors in India. Methods - This was a prospective and retrospective study in pediatric patients who had undergone surgery in our institute (JIPMER,Pondicherry). 80 cases were recruited and followed up for minimum follow up period of 1 year. The demographic profile was analysed and IHC markers were done for embroyonal tumors and glioma. Result(s): Pediatric brain tumors was equally distributed among male and females. (1:1) .Mean age of presentation was 10 years . 27.5 % of our cases were embryonal tumors,low grade glioma (16.25 % ) ,high grade glioma ( 12.5 % ) ,ependymoma and craniopharyngioma comprised 15 % of our cases each. Medulloblastoma comprised 23.75 % of cases Out of which 31.5 % had craniospinal metastasis at time of diagnosis. The most common location of SHH pathway medulloblastoma was cerebellar hemisphere and non WNT/non SHH was fourth ventricle. 45.45 % of patients with high grade glioma had recurrence .50 % of ependymoma cases were infratentorial. we had 2 cases of ganglioglioma ,one in the midbrain and other in temporal lobe .Gross total resection was achieved in 30 % ,Subtotal resection in 46.25 % and partial resection in 20 % of our cases. Outcome of patients at the end of 1 year for low and high grade glioma, ependymoma and craniopharyngioma were similar to western literature. Two patients acquired COVID 19 and died while undergoing treatment. Molecular markers like INI1, LIN28 A was highly sensitive and specific for diagnosing atypical teratoid rhabdoid tumor (ATRT) and embryonal tumor with multilayered rosettes (ETMR )respectively. Conclusion(s): Our study emphasizes the need of standardized and systemic cancer registries in India. (Figure Presented).

The sense of taste: Development, regeneration, and dysfunction.

Gustation or the sense of taste is a primary sense, which functions as a gatekeeper for substances that enter the body. Animals, including humans, ingest foods that contain appetitive taste stimuli, including those that have sweet, moderately salty and umami (glutamate) components, and tend to avoid bitter-tasting items, as many bitter compounds are toxic. Taste is mediated by clusters of heterogeneous taste receptors cells (TRCs) organized as taste buds on the tongue, and these convey taste information from the oral cavity to higher order brain centers via the gustatory sensory neurons of the seventh and ninth cranial ganglia. One remarkable aspect of taste is that taste perception is mostly uninterrupted throughout life yet TRCs within buds are constantly renewed; every 1-2 months all taste cells have been steadily replaced. In the past decades we have learned a substantial amount about the cellular and molecular regulation of taste bud cell renewal, and how taste buds are initially established during embryogenesis. Here I review more recent findings pertaining to taste development and regeneration, as well as discuss potential mechanisms underlying taste dysfunction that often occurs with disease or its treatment. This article is categorized under: Infectious Diseases > Stem Cells and Development Cancer > Stem Cells and Development Neurological Diseases > Stem Cells and Development.

Single-Cell Analysis Reveals Characteristics of Myeloid Cells in Pulmonary Pasc

Background: Although our understanding of immunopathology in the risk and severity of COVID-19 disease is evolving, a detail of immune response in long-term consequences of COVID-19 infection remains unclear. Recently, few studies have detailed the immune and cytokine profiles associated with PASC. However, dysregulation of immune system driving pulmonary PASC is still largely unknown. Method(s): To characterize the immunological features of PPASC, we performed droplet-based scRNA-sequencing using 10X genomics to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from participants naive to SARS-CoV-2 (NP, n=2) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC, n=2). Result(s): Analysis of more than 34,000 PBMCs by integrating our dataset with previously reported control datasets generated cell distribution and identified 11 immune cell types based on canonical gene expression. The proportion of myeloid-lineage cells (CD14+monocyte, CD16+monocyte, and dendritic cells) and platelets were increased in PPASC compared with those of NP. Specifically, PPASC displayed up-regulation of VEGFA and transcription factors, such as ATF2, ELK, and SMAD in myeloid-lineage cells. Also, TGF-beta and WNT signaling pathways were up-regulated in these cell population. Cell-cell interaction analysis identified that myeloid-lineage cells in PPASC participated in regulation of fibrosis and immune response, such as VEGFA (increased) and MIF (decreased) interactions. Conclusion(s): Together, this study provides high-resolution insights into immune landscape in PPASC. Our results emphasize differences in myeloid lineage-mediated fibrosis and immunity between PPASC and NP, suggesting they could act as potential pathological drivers of PPASC. (Figure Presented).

Wnt 2022 EMBO | the Company of Biologists workshop and Yamada conference.

Wnt2022 was held on November 15th-19th, 2022, in Awaji Yumebutai International Conference Center, Hyogo Prefecture, Japan, as an in-person meeting for the first time in last 3 years. Wnt signaling is a highly conserved pathway among various species. Since Wnt1 was discovered in 1982, a number of studies using many model animals and human samples have revealed that Wnt signaling plays crucial roles in embryonic development, tissue morphogenesis, and regeneration, as well as many other physiological and pathological processes. Since the year 2022 marks the 40th anniversary of Wnt research, we aimed to look back at our research progress and discuss the future direction of this field. The scientific program consisted of plenary lectures, invited talks, short talks selected from abstracts, and poster sessions. Whereas several different Wnt meetings have been held almost every year in Europe and the United States, this was the first Wnt meeting convened in Asia. Therefore, Wnt2022 was highly anticipated to bring together leaders and young scientists from Europe, the United States, and especially Asia and Oceania. In fact, 148 researchers from 21 countries attended this meeting. Although there were travel and administrative restrictions due to COVID-19, the meeting was highly successful in enabling face-to-face discussions.

Lung fibrosis: Post-COVID-19 complications and evidences.

BACKGROUND: COVID 19, a lethal viral outbreak that devastated lives and the economy across the globe witnessed non-compensable respiratory illnesses in patients. As been evaluated in reports, patients receiving long-term treatment are more prone to acquire Pulmonary Fibrosis (PF). Repetitive damage and repair of alveolar tissues increase oxidative stress, inflammation and elevated production of fibrotic proteins ultimately disrupting normal lung physiology skewing the balance towards the fibrotic milieu. AIM: In the present work, we have discussed several important pathways which are involved in post-COVID PF. Further, we have also highlighted the rationale for the use of antifibrotic agents for post-COVID PF to decrease the burden and improve pulmonary functions in COVID-19 patients. CONCLUSION: Based on the available literature and recent incidences, it is crucial to monitor COVID-19 patients over a period of time to rule out the possibility of residual effects. There is a need for concrete evidence to deeply understand the mechanisms responsible for PF in COVID-19 patients.

Automated SSHHPS Analysis Predicts a Potential Host Protein Target Common to Several Neuroinvasive (+)ssRNA Viruses.

Within the viral genome, short stretches of homologous host pathogen sequences (SSHHPS) span the protease cleavage sites. To identify host proteins that may be cleaved during infection, we searched the human proteome for viral protease cleavage sites (~20 amino acids). We developed a sequence-to-symptom tool, automating the search and pairing process. We used the viral protein sequence, PHI-BLAST, and UniProt database for gene ontologies and disease relationships. We applied the tool to nine neuroinvasive viruses: Venezuelan and Eastern Equine encephalitis virus (VEEV, EEEV); severe acute respiratory syndrome (SARS, SARS-CoV-2); Middle East respiratory syndrome (MERS); EV-71; Japanese encephalitis virus (JEV); West Nile (WNV); and Zika (ZIKV). A comparison of the hits identified a protein common to all nine viruses called ADGRA2 (GPR124). ADGRA2 was a predicted hit of the 3CL main protease and papain-like protease (PLpro) of SARS-CoV-2. ADGRA2 is an adhesion G protein-coupled receptor and a key endothelial regulator of brain-specific angiogenesis. It is a Wnt7A/Wnt7B specific coactivator of beta-catenin signaling and is essential for blood-brain barrier (BBB) integrity in central nervous system (CNS) diseases. We show the cleavage of the predicted sequences in MYOM1, VWF by the SARS-CoV-2 PLpro; DNAH8 (dynein) by the MERS PLpro; ADGRA2 by the alphaviral VEEV nsP2 protease; and POT1 by the SARS-CoV-2 and MERS PLpro.

Amelioration of Lung Fibrosis by Total Flavonoids of Astragalus via Inflammatory Modulation and Epithelium Regeneration.

Idiopathic Pulmonary Fibrosis (IPF) is identifiable by the excessive increase of mesenchyme paired with the loss of epithelium. Total flavonoids of Astragalus (TFA), the main biologically active ingredient of the traditional Chinese medicine, Astragalus membranaceus (Huangqi), shows outstanding effects on treating pulmonary disorders, including COVID-19-associated pulmonary dysfunctions. This study was designed to evaluate the efficacy of TFA on treating pulmonary fibrosis and the possible mechanisms behind these effects. A549 cells were treated with TGF-[Formula: see text]1 and TFA to observe the potential effects of TFA on regulating alveolar epithelial cell proliferation, TGF-[Formula: see text]1-induced EMT, and the underlying mechanisms in vitro. Then, mouse pulmonary fibrosis was induced with a single intra-tracheal injection of bleomycin, and TFA was administrated by i.p. injection. Lung fibrosis was evaluated through histological and molecular analyses, and the possible mechanisms were explored using immunological methods. The results demonstrated that TFA could promote cell proliferation but inhibit TGF-[Formula: see text]1-induced EMT on A549 cells. TFA attenuated BLM-induced pulmonary fibrosis in mice by modulating inflammatory infiltration and M2 macrophage polarization; it furthermore modulated EMT through regulating the TGF-[Formula: see text]1/Smad pathway. In addition, TFA augmented the expression of the Wnt7b protein, which plays an important role in alveolar epithelium reparation. In conclusion, TFA alleviated bleomycin-induced mouse lung fibrosis by preventing the fibrotic response and increasing epithelium regeneration.

Rice as one of antioxidant source for farming family in COVID-19 pandemic: a case study from West Nusa Tenggara Indonesia

The main food consumption of farming families is an important concern during the pandemic. Farmers in West Nusa Tenggara (WNT) survive with the availability of rice to support household health and food security during the pandemic. In addition to its nutritional content, rice also contains phenolic compounds and has antioxidant activity. This study aims are to measure the frequency of rice consumption, food variety, varieties of rice consumed daily during the pandemic in WNT, as well as the antioxidant properties of several rice varieties grown in WNT. This study was conducted from September 2020 to June 2021 in East Lombok, Sumbawa and Bima Regencies, WNT Province, Indonesia using a survey approach. The data collection techniques were observation, Focus Group Discussion, recording, interviews with 74 respondents with a semi-structured questionnaire and study literature related to the nutritional content and bioactive compound of the rice. Quantitative data was tabulated to determine the frequency and average then descriptively analyzed, while qualitative data was thematically analysed. The most consumed rice varieties are seen from the production data of seed breeders in the WNT region, the phenolic content was determined using Folin–Ciocalteu, antioxidant activity was examined using DPPH assay. The result showed that the highest portion of food consumed by farmer households in WNT is rice. The most variety of rice produced by breeders is the Inpari 32 variety. There are about 97% of farmers consume rice for 3 times a day, while 3% of the remaining consume 2 times a day of rice. Food variety includes 7.9% vegetable-rice and 92.1% rice-vegetables-meat protein. The results of the analysis of antioxidant properties and phenolic content in rice is depending on the variety. The antioxidant properties of the Jeliteng, Baroma, Pamelen, Nutrizinc and Inpari 32 rice varieties were 44.85±0.51%, 9.87±1.55%, 9.96±1.22%, 9.75±1.09%, and 14.305±1.24%, respectively, while the phenolic contents were 9.76±0.09, 4.23±0.03, 4.48±0.02, 4.64± 0.07, 4.58±0.42 mg GAE/g dryrice extract, respectively. The results of this study indicate that rice has been used as one of antioxidants source for farming families during the pandemic.

Transmissible Gastroenteritis Virus Infection Promotes the Self-Renewal of Porcine Intestinal Stem Cells via Wnt/ß-Catenin Pathway.

Intestinal stem cells (ISCs) play an important role in tissue repair after injury. A recent report delineates the effect of transmissible gastroenteritis virus (TGEV) infection on the small intestine of recovered pigs. However, the mechanism behind the epithelium regeneration upon TGEV infection remains unclear. To address this, we established a TGEV infection model based on the porcine intestinal organoid monolayer. The results illustrated that the porcine intestinal organoid monolayer was susceptible to TGEV. In addition, the TGEV infection initiated the interferon and inflammatory responses following the loss of absorptive enterocytes and goblet cells. However, TGEV infection did not disturb epithelial integrity but induced the proliferation of ISCs. Furthermore, TGEV infection activated the Wnt/ß-catenin pathway by upregulating the accumulation and nuclear translocation of ß-catenin, as well as promoting the expression of Wnt target genes, such as C-myc, Cyclin D1, Mmp7, Lgr5, and Sox9, which were associated with the self-renewal of ISCs. Collectively, these data demonstrated that the TGEV infection activated the Wnt/ß-catenin pathway to promote the self-renewal of ISCs and resulted in intestinal epithelium regeneration. IMPORTANCE The intestinal epithelium is a physical barrier to enteric viruses and commensal bacteria. It plays an essential role in maintaining the balance between the host and intestinal microenvironment. In addition, intestinal stem cells (ISCs) are responsible for tissue repair after injury. Therefore, prompt self-renewal of intestinal epithelium will facilitate the rebuilding of the physical barrier and maintain gut health. In the manuscript, we found that the transmissible gastroenteritis virus (TGEV) infection did not disturb epithelial integrity but induced the proliferation of ISCs and facilitated epithelium regeneration. Detailed mechanism investigations revealed that the TGEV infection activated the Wnt/ß-catenin pathway to promote the self-renewal of ISCs and resulted in intestinal epithelium regeneration. These findings will contribute to understanding the mechanism of intestinal epithelial regeneration and reparation upon viral infection.

Wnt5a/ß-catenin axis is involved in the downregulation of AT2 lineage by PAI-1.

Failure to regenerate injured alveoli functionally and promptly causes a high incidence of fatality in coronavirus disease 2019 (COVID-19). How elevated plasminogen activator inhibitor-1 (PAI-1) regulates the lineage of alveolar type 2 (AT2) cells for re-alveolarization has not been studied. This study aimed to examine the role of PAI-1-Wnt5a-ß catenin cascades in AT2 fate. Dramatic reduction in AT2 yield was observed in Serpine1Tg mice. Elevated PAI-1 level suppressed organoid number, development efficiency, and total surface area in vitro. Anti-PAI-1 neutralizing antibody restored organoid number, proliferation and differentiation of AT2 cells, and ß-catenin level in organoids. Both Wnt family member 5A (Wnt5a) and Wnt5a-derived N-butyloxycarbonyl hexapeptide (Box5) altered the lineage of AT2 cells. This study demonstrates that elevated PAI-1 regulates AT2 proliferation and differentiation via the Wnt5a/ß catenin cascades. PAI-1 could serve as autocrine signaling for lung injury repair.

Transcriptomic analysis reveals crucial regulatory roles of immediate-early response genes and related signaling pathways in coronavirus infectious bronchitis virus infection.

Coronavirus infection of cells differentially regulates the expression of host genes and their related pathways. In this study, we present the transcriptomic profile of cells infected with gammacoronavirus infectious bronchitis virus (IBV). In IBV-infected human non-small cell lung carcinoma cells (H1299 cells), a total of 1162 differentially expressed genes (DEGs), including 984 upregulated and 178 downregulated genes, was identified. These DEGs were mainly enriched in MAPK and Wnt signaling pathways, and 5 out of the 10 top upregulated genes in all transcripts were immediate-early response genes (IEGs). In addition, the induction of 11 transcripts was validated in IBV-infected H1299 and Vero cells by RT-qPCR. The accuracy, reliability and genericity of the transcriptomic data were demonstrated by functional characterization of these IEGs in cells infected with different coronaviruses in our previous publications. This study provides a reliable transcriptomic profile of host genes and pathways regulated by coronavirus infection.

Dipeptidylpeptidase (DPP)-4 inhibitor therapy increases circulating levels of antiinflammatory soluble frizzle receptor protein (sFRP)-5 which is decreased in severe COVID-19 disease

Background and Aim Obesity and type 2 diabetes (T2D) show an increased risk for a severe COVID-19 disease. Treatment with DPP4 inhibitor (DPP4i) results in reduced mortality and better clinical outcome. Here, we aimed to identify potential mechanisms for the observed DPP4i effect in COVID-19. Methods We compared T2D subjects with (cases) and without (controls) DPP4i treatment (N=69), as well as patients hospitalised for severe COVID-19 and healthy controls (N=34) with regard to serum concentrations of soluble frizzle receptor protein 5 (sFRP5) using univariate statistics. Furthermore, we isolated pre-adipocytes, mature adipocytes and macrophages from adipose tissue biopsies (N=100) and performed western-blotting for sFRP5 and Wnt5a expression. Results In T2D patients, we identified a significant increase of the anti-inflammatory adipokine sFRP5 in relation to DPP4 inhibition. sFRP5 is a specific antagonist to Wnt5a, a glycopeptide secreted by adipose tissue macrophages acting proinflammatory in various diseases. We therefore examined sFRP5 levels in patients hospitalised for severe COVID-19 and found significant lower levels compared to healthy controls. Since sFRP5 might consequently be a molecular link for the beneficial effects of DPP4i in COVID-19, we further aimed to identify the exact source of sFRP5 in adipose tissue on cellular level. Results from western-blotting in adipose tissues showed a sFRP5 expression specifically in mature adipocytes of subcutaneous and omental adipose tissue. Conclusion In summary, our data suggest that DPP4i increase serum levels of anti-inflammatory sFRP5 which might be beneficial in COVID-19, reflecting a state of sFRP5 deficiency.

A Prospective Characterization of Metabolic and Metabolomic Profiles of COVID-19–Associated New-Onset Diabetes Patients Presenting with DKA from India

Background: Recent evidence suggests a bidirectional relationship between COVID-infection and new-onset diabetes (NOD) presenting with DKA. Methodology: This one-year prospective study comprised of 29 COVID-negative DKA (controls) and 52 COVID-positive-DKA patients (18 NOD, 15 T1DM ,T2DM) . NOD were previously normoglycemic and negative for GAD/IA-2/ZnT8 autoantibodies. After 75g- OGTT with estimation of glucose, C-peptide, FFA and insulin at 0,15, 30,45, 60,90 ,120, 150 and 180minutes, Insulin secretion rate (ISR) [C-peptide-deconvolution] , Hepatic insulin sensitivity [AUC-glucose × AUC-insulin during first 30-minutes of OGTT ], Peripheral insulin sensitivity [ dG/dt ÷ mean plasma insulin concentration;dG/dt rate of decline in plasma glucose concentration]were calculated alongwith Metabolomics and Adipose tissue gene expression. All tests were performed at admission and 4, 8, and 12-months of followup. Results: At baseline, ISR in NOD was significantly reduced than controls (p=0.001) but similar to T1DM (p=0.15) . Nearly 83% (n=17) of NOD with DKA had near-complete recovery of ISR on follow-up compared to T1DM (all p<0.01) ,with non-remitters (n=3) having significantly worse admission Hba1c and IL-6 (all p<0.01) . NOD had significantly increased hepatic and peripheral insulin resistance compared to T1DM (all p<0.05) ,but similar to T2DM (all p>0.05) . Their Metabolomics revealed increased inflammatory phosphatidylcholines, that correlated with peripheral glucose uptake (p<0.01) ,while RNA sequencing showed significantly enhanced WNT5A , TLR4 (Toll-like Receptor-4) and RETN (resistin) than T1DM and T2DM (both p=0.001) . Conclusion: Our study provides novel insights into COVID-associated NOD with DKA. Majority have near-complete recovery of insulin secretion while simultaneous multi-tissue insulin resistance and inflammatory adipose tissue profiles persist as drivers of hyperglycemia.

Endothelial ß-Catenin Deficiency Causes Blood-Brain Barrier Breakdown via Enhancing the Paracellular and Transcellular Permeability.

Disruption of the blood-brain barrier (BBB) causes or contributes to neuronal dysfunction and several central nervous system (CNS) disorders. Wnt/ß-catenin signaling is essential for maintaining the integrity of the adult BBB in physiological and pathological conditions, including stroke. However, how the impairment of the endothelial Wnt/ß-catenin signaling results in BBB breakdown remains unclear. Furthermore, the individual contributions of different BBB permeability-inducing mechanisms, including intercellular junction damage, endothelial transcytosis, and fenestration, remains unexplored. Here, we induced ß-catenin endothelial-specific conditional knockout (ECKO) in adult mice and determined its impact on BBB permeability and the underlying mechanism. ß-catenin ECKO reduced the levels of active ß-catenin and the mRNA levels of Wnt target genes in mice, indicating downregulation of endothelial Wnt/ß-catenin signaling. ß-catenin ECKO mice displayed severe and widespread leakage of plasma IgG and albumin into the cerebral cortex, which was absent in wild-type controls. Mechanistically, both the paracellular and transcellular transport routes were disrupted in ß-catenin ECKO mice. First, ß-catenin ECKO reduced the tight junction protein levels and disrupted the intercellular junction ultrastructure in the brain endothelium. Second, ß-catenin ECKO substantially increased the number of endothelial vesicles and caveolae-mediated transcytosis through downregulating Mfsd2a and upregulating caveolin-1 expression. Interestingly, fenestration and upregulated expression of the fenestration marker Plvap were not observed in ß-catenin ECKO mice. Overall, our study reveals that endothelial Wnt/ß-catenin signaling maintains adult BBB integrity via regulating the paracellular as well as transcellular permeability. These findings may have broad applications in understanding and treatment of CNS disorders involving BBB disruption.

"Reframing" dopamine signaling at the intersection of glial networks in the aged Parkinsonian brain as innate Nrf2/Wnt driver: Therapeutical implications.

Dopamine (DA) signaling via G protein-coupled receptors is a multifunctional neurotransmitter and neuroendocrine-immune modulator. The DA nigrostriatal pathway, which controls the motor coordination, progressively degenerates in Parkinson's disease (PD), a most common neurodegenerative disorder (ND) characterized by a selective, age-dependent loss of substantia nigra pars compacta (SNpc) neurons, where DA itself is a primary source of oxidative stress and mitochondrial impairment, intersecting astrocyte and microglial inflammatory networks. Importantly, glia acts as a preferential neuroendocrine-immune DA target, in turn, counter-modulating inflammatory processes. With a major focus on DA intersection within the astrocyte-microglial inflammatory network in PD vulnerability, we herein first summarize the characteristics of DA signaling systems, the propensity of DA neurons to oxidative stress, and glial inflammatory triggers dictating the vulnerability to PD. Reciprocally, DA modulation of astrocytes and microglial reactivity, coupled to the synergic impact of gene-environment interactions, then constitute a further level of control regulating midbrain DA neuron (mDAn) survival/death. Not surprisingly, within this circuitry, DA converges to modulate nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/ß-catenin signaling, a key pathway for mDAn neurogenesis, neuroprotection, and immunomodulation, adding to the already complex "signaling puzzle," a novel actor in mDAn-glial regulatory machinery. Here, we propose an autoregulatory feedback system allowing DA to act as an endogenous Nrf2/Wnt innate modulator and trace the importance of DA receptor agonists applied to the clinic as immune modifiers.

Cannabidiol and SARS-CoV-2 Infection.

Cannabidiol (CBD) can prevent the inflammatory response of SARS-CoV-2 spike protein in Caco-2-cells. This action is coupled with the inhibition of IL-1beta, IL-6, IL-18, and TNF-alpha, responsible for the inflammatory process during SARS-CoV-2 infection. CBD can act on the different proteins encoded by SARS-CoV-2 and as an antiviral agent to prevent the viral infection. Furthermore, recent studies have shown the possible action of CBD as an antagonist of cytokine release syndromes. In the SARS-CoV-2 pathophysiology, the angiotensin-converting enzyme 2 (ACE2) seems to be the key cell receptor for SARS-CoV-2 infection. The WNT/ß-catenin pathway and PPARγ interact in an opposite manner in many diseases, including SARS-CoV-2 infection. CBD exerts its activity through the interaction with PPARγ in SARS-CoV-2 infection. Thus, we can hypothesize that CBD may counteract the inflammatory process of SARS-CoV-2 by its interactions with both ACE2 and the interplay between the WNT/ß-catenin pathway and PPARγ. Vaccines are the only way to prevent COVID-19, but it appears important to find therapeutic complements to treat patients already affected by SARS-CoV-2 infection. The possible role of CBD should be investigated by clinical trials to show its effectiveness.

Single cell profiling in COVID-19 associated acute kidney injury reveals patterns of tubule injury and repair in human

Background: Acute Kidney Injury (AKI) affects up to one in two critically ill patients. The cellular mechanisms of kidney tubule repair after acute kidney injury are poorly characterized in humans. Methods: We recruited 5 patients admitted to the Geneva University Hospital's Intensive Care Unit for severe COVID19 and experiencing AKI. For each of them, a kidney biopsy was performed before the planned withdrawal of resuscitation measures. We further applied single-cell RNA sequencing to analyze the kidney in the first days after acute injury. Results: After data processing and quality control, we obtained 20,165 single-cell transcriptomes. The most prominent finding in the snRNAseq analyses was in the proximal tubule (PT) compartment. We defined two cell populations corresponding to mature and undifferentiated PT cells, connected by two cell state transitions (Figure 1). Undifferentiated PT cells display an injured pattern characterized by metabolic impairment, reduction of the tubule transport function, and expression of injury markers confirmed in immunochemistry. We found that tubule repair follows two converging patterns involving the plasticity of mature tubule cells and the expansion and differentiation of progenitor-like cells. Tubule repair by cell plasticity displayed substantial similarities among mice and men and determined the transient expansion of undifferentiated tubule cells with altered functional and metabolic properties. Progenitorlike cells marked by PROM1 proliferated in response to injury and followed a differentiation process characterized by the sequential activation of the WNT, NOTCH, and HIPPO signaling pathways. Conclusions: Here we generated the first map of PT injury and repair in humans. Taken together, our analyses reveal cell states transitions and fundamental cellular hierarchies underlying kidney injury and repair in patients.

Functional Genomics of PRUNE1 in Neurodevelopmental Disorders (NDDs) Tied to Medulloblastoma (MB) and Other Tumors.

We analyze the fundamental functions of Prune_1 in brain pathophysiology. We discuss the importance and maintenance of the function of Prune_1 and how its perturbation influences both brain pathological conditions, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; OMIM: 617481), and tumorigenesis of medulloblastoma (MB) with functional correlations to other tumors. A therapeutic view underlying recent discoveries identified small molecules and cell penetrating peptides to impair the interaction of Prune_1 with protein partners (e.g., Nm23-H1), thus further impairing intracellular and extracellular signaling (i.e., canonical Wnt and TGF-ß pathways). Identifying the mechanism of action of Prune_1 as responsible for neurodevelopmental disorders (NDDs), we have recognized other genes which are found overexpressed in brain tumors (e.g., MB) with functional implications in neurodevelopmental processes, as mainly linked to changes in mitotic cell cycle processes. Thus, with Prune_1 being a significant target in NDDs, we discuss how its network of action can be dysregulated during brain development, thus generating cancer and metastatic dissemination.

Cancer chemopreventive role of fisetin: Regulation of cell signaling pathways in different cancers.

It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive compounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/ß-catenin, NF-κB and TRAIL/TRAIL-R by fisetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fisetin regulated autophagy in different cancers. In addition, this review also covers fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated inflammations. Furthermore, fisetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fledge and well-designed clinical trials of fisetin in different cancers. However, we still have to comprehensively analyze and fully unlock pharmacological potential of fisetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.