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An mPOA-ARCAgRP pathway modulates cold-evoked eating behavior

Cell reports

2021 Aug 10

Yang, S;Tan, YL;Wu, X;Wang, J;Sun, J;Liu, A;Gan, L;Shen, B;Zhang, X;Fu, Y;Huang, J;
PMID: 34380037 | DOI: 10.1016/j.celrep.2021.109502

Enhanced appetite occurs as a means of behavioral thermoregulation at low temperature. Neural circuitry mediating this crosstalk between behavioral thermoregulation and energy homeostasis remains to be elucidated. We find that the hypothalamic orexigenic agouti-related neuropeptide (AgRP) neurons in the arcuate nucleus (ARC) are profoundly activated by cold exposure. The calcium signals in ARCAgRP neurons display an immediate-response pattern in response to cold stimulation. Cold-responsive neurons in the medial preoptic area (mPOA) make excitatory synapses onto ARCAgRP neurons. Inhibition of either ARCAgRP neurons or ARC-projecting mPOA neurons attenuates cold-evoked feeding, while activation of the mPOA-to-ARC projection increases food intake. These findings reveal an mPOA-ARCAgRP neural pathway that modulates cold-evoked feeding behavior.

Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

Communications biology

2021 Aug 10

Rada, M;Kapelanski-Lamoureux, A;Petrillo, S;Tabariès, S;Siegel, P;Reynolds, AR;Lazaris, A;Metrakos, P;
PMID: 34376784 | DOI: 10.1038/s42003-021-02481-8

Colorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement. The replacement lesions obtain their blood supply through vessel co-option, wherein the cancer cells hijack pre-existing blood vessels of the surrounding liver tissue. Consequentially, anti-angiogenic therapies are less efficacious in CRCLM patients with replacement lesions. However, the mechanisms which drive vessel co-option in the replacement lesions are unknown. Here, we show that Runt Related Transcription Factor-1 (RUNX1) overexpression in the cancer cells of the replacement lesions drives cancer cell motility via ARP2/3 to achieve vessel co-option. Furthermore, overexpression of RUNX1 in the cancer cells is mediated by Transforming Growth Factor Beta-1 (TGFβ1) and thrombospondin 1 (TSP1). Importantly, RUNX1 knockdown impaired the metastatic capability of colorectal cancer cells in vivo and induced the development of angiogenic lesions in liver. Our results confirm that RUNX1 may be a potential target to overcome vessel co-option in CRCLM.

Ulcerative colitis: shedding light on emerging agents and strategies in preclinical and early clinical development

Expert opinion on investigational drugs

2021 Aug 10

Caballol, B;Gudiño, V;Panes, J;Salas, A;
PMID: 34365869 | DOI: 10.1080/13543784.2021.1965122

Ulcerative colitis (UC) is an inflammatory disease of the large intestine. Progress in preclinical therapeutic target discovery and clinical trial design has resulted in the approval of new therapies. Nonetheless, remission rates remain below 30% thus underlining the need for novel, more effective therapies.This paper reviews current experimental techniques available for drug testing in intestinal inflammation and examines new therapies in clinical development for the treatment of UC. The authors searched the literature for 'ulcerative colitis' AND 'preclinical' OR 'drug target/drug name' (i.e. infliximab, vedolizumab, IL-12, IL-23, JAK, etc.). Studies that included preclinical in vivo or in vitro experiments are discussed. The clinicaltrial.gov site was searched for 'ulcerative colitis' AND 'Recruiting' OR 'Active, not recruiting' AND 'Interventional (Clinical Trial)' AND 'early phase 1' OR 'phase 1' OR 'phase 2' OR 'phase 3.'Using in vivo, ex vivo, and/or in vitro models could increase the success rates of drugs moving to clinical trials, and hence increase the efficiency of this costly process. Selective JAK1 inhibitors, S1P modulators, and anti-p19 antibodies are the most promising options to improve treatment effectiveness. The development of drugs with gut-restricted exposure may provide increased efficacy and an improved safety.

Analysis of Factors Related to Lymph Node Metastasis in Early-Stage Type 1 Endometrial Cancer: Verifying the Clinical Value of Positive Threshold of the Immunohistochemical Parameter Ki67

Cancer management and research

2021 Aug 10

Jiang, P;Yuan, R;
PMID: 34413681 | DOI: 10.2147/CMAR.S316211

Lymph node metastasis (LNM) is an important reference indicator for the prognosis of endometrial cancer (EC). Even in patients with early low-risk EC, many people still have LNM. The purpose of this study was to investigate the related factors influencing LNM in early-stage EC and determine the optimal positive threshold of immunohistochemical parameter Ki67 for predicting LNM, providing auxiliary reference indicators for clinical diagnosis and treatment.The clinicopathological data of 651 patients with "apparent" early-stage EC who underwent standard surgical treatment were included. Univariate and multivariate logistics regression were used to analyze the correlation between each clinicopathological factor and LNM. Receiver operating characteristic curve (ROC curve) and Youden index were used to determine the optimal positive threshold of Ki67 for predicting LNM. Finally, correlation between Ki67 and various clinicopathological factors was analyzed, and the predictive value of each prognostic factor was compared.Multivariate analysis found that histologic grade (P=0.023), lymphatic vessel space invasion (LVSI) (P < 0.001), serological index Ca125 (P=0.002), immunohistochemical parameter Ki67 (P < 0.001), ER (P < 0.001) and P53 (P=0.001) were independent prognostic factors of LNM. ROC curve and Youden index showed that the optimal positive thresholds of Ki67 to predict LNM were 40%. Based on this, ROC curve showed that the area under the curve (AUC) of Ki67 (AUC=0.714) was larger than other single predictors, and Ki67 combined with other predictors can significantly increase the AUC value (AUC= 0.847 and 0.868, respectively).Ki67 was an important predictor for predicting the LNM in early-stage EC and taking a positive percentage of about 40% can be used as the positive threshold of the immunohistochemical parameter Ki67. On this basis, Ki67 combined with other predictive indicators can significantly improve prediction performance and can be used for segmentally predicting LNM of early-stage EC.

ADAMTS18 deficiency leads to preputial gland hypoplasia and fibrosis in male mice

Reproductive biology

2021 Aug 10

Lin, X;Wu, T;Wang, L;Dang, S;Zhang, W;
PMID: 34388417 | DOI: 10.1016/j.repbio.2021.100542

ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are a family of 19 secreted zinc metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM) during development, morphogenesis, tissue repair, and remodeling. ADAMTS18 is a poorly characterized member of the ADAMTS family. Previously, ADAMTS18 was found to participate in the development of female reproductive tract in mice. However, whether ADAMTS18 also plays a role in the development of male reproductive system remains unclear. In this study, Adamts18 mRNA was found to be highly expressed in the basal cells of the developing preputial gland. Male Adamts18 knockout (Adamts18-/-) mice exhibit abnormal preputial gland morphogenesis, including reduced size and sharp outline. Histological analyses of preputial gland from 2-week-old male Adamts18-/- mice showed significant atrophy of the whole gland. Preputial glands from 7 months and older Adamts18-/- mice appeared macroscopic swelling on their surface. Histologically, preputial gland swelling is characterized by tissue fibrosis and thicker keratinized squamous cell layer. Preputial gland lesions in age-matched male Adamts18+/+ mice were barely detected. ADAMTS18 deficiency does not lead to significant changes in morphogenesis of prostate and testis in male mice. These results indicate that ADAMTS18 is required for normal morphogenesis and homeostasis of the preputial gland in male mice.

Neutrophil-epithelial interactions augment infectivity and pro-inflammatory responses to SARS-CoV-2 infection

bioRxiv : the preprint server for biology

2021 Aug 10

Calvert, BA;Quiroz, EJ;Lorenzana, Z;Doan, N;Kim, S;Senger, CN;Wallace, WD;Salomon, MP;Henley, JE;Ryan, AL;
PMID: 34401877 | DOI: 10.1101/2021.08.09.455472

In response to viral infection, neutrophils release inflammatory mediators as part of the innate immune response, contributing to pathogen clearance through virus internalization and killing. Pre-existing co-morbidities, correlating to incidence of severe COVID-19, are associated with chronic airway neutrophilia and examination of COVID-19 lung tissue revealed a series of epithelial pathologies associated with infiltration and activation of neutrophils. To determine the impact of neutrophil-epithelial interactions on the infectivity and inflammatory response to SARS-CoV-2 infection, we developed a co-culture model of airway neutrophilia. We discovered that SARS-CoV-2 infection of the airway epithelium alone does not result in a notable release of pro-inflammatory cytokines, however in the presence of neutrophils, the inflammatory response is both polarized and significantly augmented, epithelial barrier integrity in impaired and viral load of the airway epithelium increased. This study reveals a key role for neutrophil-epithelial interactions in determining inflammation, infectivity, and outcomes in response to SARS-CoV-2 infection.We have developed a model to study neutrophil-epithelial interactions which better reflects the in vivo situation than monocultures Neutrophils significantly augment SARS-CoV-2 mediated, pro-inflammatory cytokine release from the epithelium indicating a key interactionSARS-CoV-2 infection leads to a polarized inflammatory response in differentiated airway epitheliumDisruption of the epithelial barrier via addition of neutrophils or cytokines leads to increased infectionStudy reveals a key role for neutrophil-epithelial interactions in determining outcome/infectivity.

Mutually Exclusive Expression of COL11A1 by CAFs and Tumour Cells in a Large panCancer and a Salivary Gland Carcinoma Cohort

Head and neck pathology

2021 Aug 10

Arolt, C;Hoffmann, F;Nachtsheim, L;Wolber, P;Guntinas-Lichius, O;Buettner, R;von Eggeling, F;Quaas, A;Klußmann, JP;
PMID: 34378164 | DOI: 10.1007/s12105-021-01370-0

Procollagen 11A1 (COL11A1) is a central component of the extracellular matrix in many carcinomas, which is considered to be mainly produced by cancer associated fibroblasts (CAFs). As COL11A1 expression correlates with adverse prognosis and is implicated in chemoresistance, it is a promising putative target. For the first time, we used RNA in-situ hybridization to systematically identify the cells that produce COL11A1 in the ten most prevalent carcinoma types, lymphomas (n = 275) and corresponding normal tissue (n = 55; panCancer cohort). Moreover, as most salivary gland carcinomas (SGC) display distinct stromal architectures, we also analysed 110 SGC. The corresponding protein formation of COL11A1 was determined by MALDI-TOF-MS-Imaging. We report that colon, breast and salivary duct carcinomas are highly infiltrated by COL11A1 positive CAFs (CAFsCOL11A1) and might thus be promising candidates for antidesmoplastic or COL11A1-targeted therapies. The amount of CAFsCOL11A1 correlated significantly with tumour grade, tumour stage and nodal spread in the panCancer cohort. Significant associations between CAFsCOL11A1 and vascular invasion, perineural spread and nodal spread were observed in the SGC cohort. Also, we discovered that tumour cells of intercalated duct derived SGC and CAFs produce COL11A1 in a mutually exclusive manner. Our findings represent a novel mode of extracellular matrix production in carcinomas and could be highly relevant in the future. Our findings elucidate the mode of COL11A1 expression in very different carcinoma types and may aid to categorise tumours in the setting of possible future COL11A1-related therapies.

FANCI plays an essential role in spermatogenesis and regulates meiotic histone methylation

Cell death & disease

2021 Aug 09

Xu, L;Xu, W;Li, D;Yu, X;Gao, F;Qin, Y;Yang, Y;Zhao, S;
PMID: 34373449 | DOI: 10.1038/s41419-021-04034-7

FANCI is an essential component of Fanconi anemia pathway, which is responsible for the repair of DNA interstrand cross-links (ICLs). As an evolutionarily related partner of FANCD2, FANCI functions together with FANCD2 downstream of FA core complex. Currently, growing evidences showed that the essential role of FA pathway in male fertility. However, the underlying mechanisms for FANCI in regulating spermatogenesis remain unclear. In the present study, we found that the male Fanci-/- mice were sterile and exhibited abnormal spermatogenesis, including massive germ cell apoptosis in seminiferous tubules and dramatically decreased number of sperms in epididymis. Besides, FANCI deletion impaired maintenance of undifferentiated spermatogonia. Further investigation indicated that FANCI was essential for FANCD2 foci formation and regulated H3K4 and H3K9 methylation on meiotic sex chromosomes. These findings elucidate the role and mechanism of FANCI during spermatogenesis in mice and provide new insights into the etiology and molecular basis of nonobstructive azoospermia.

Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 inhibitors TBA-7371, PBTZ169 and OPC-167832

Antimicrobial agents and chemotherapy

2021 Aug 09

Robertson, GT;Ramey, ME;Massoudi, LM;Carter, CL;Zimmerman, M;Kaya, F;Graham, BG;Gruppo, V;Hastings, C;Woolhiser, LK;Scott, DWL;Asay, BC;Eshun-Wilson, F;Maidj, E;Podell, BK;Vásquez, JJ;Lyons, MA;Dartois, V;Lenaerts, AJ;
PMID: 34370580 | DOI: 10.1128/AAC.00583-21

Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action are DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169 and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology, and perform comprehensive analysis of plasma, lung and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after two months of treatment. Superior efficacy was observed for OPC-167832 even at low dose levels, which can be attributed to its low MIC, favorable distribution and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.

LncRNA CDKN2B-AS1 hinders the proliferation and facilitates apoptosis of ox-LDL-induced vascular smooth muscle cells via the ceRNA network of CDKN2B-AS1/miR-126-5p/PTPN7

International journal of cardiology

2021 Aug 09

Li, J;Chen, J;Zhang, F;Li, J;An, S;Cheng, M;Li, J;
PMID: 34384839 | DOI: 10.1016/j.ijcard.2021.08.009

The patterns of lncRNA CDKN2B-AS1 in coronary heart disease (CHD) have been extensively studied. This study investigated the competing endogenous RNA (ceRNA) network of CDKN2B-AS1 in coronary atherosclerosis (CAS).Microarray analyses were performed to screen out the CHD-related lncRNAs (CDKN2B-AS1) and the downstream microRNAs (miR-126-5p). The expression of CDKN2B-AS1 in serum of patients with CHD and healthy volunteers was detected. Vascular smooth muscle cells (VSMCs) were treated with oxidized low density lipoprotein (ox-LDL) to establish cell model. Then pcDNA-CDKN2B-AS1 and/or miR-126-5p mimic were transfected into ox-LDL-treated VSMCs to estimate cell proliferation, apoptosis and inflammation. The ceRNA network of CDKN2B-AS1 along with the possible pathway in CHD was testified.CDKN2B-AS1 expression was low in patients with CHD and ox-LDL-treated VSMCs. Upon CDKN2B-AS1 overexpression, TNF-α, NF-κB and IL-1β levels in VSMCs were decreased, the proliferation of VSMCs was inhibited and the apoptosis rate was increased. Overexpression of miR-126-5p could reverse these trends. CDKN2B-AS1 as a ceRNA competitively bound to miR-126-5p to upregulate PTPN7. CDKN2B-AS1 inhibited VSMC proliferation and accelerated apoptosis by inhibiting the PI3K-Akt pathway.LncRNA CDKN2B-AS1 upregulates PTPN7 by absorbing miR-126-5p and inhibits the PI3K-Akt pathway, thus hindering the proliferation and accelerating apoptosis of VSMCs induced by ox-LDL, thus being a therapeutic approach for CAS.

Connexin mRNA distribution in adult mouse kidneys

Pflugers Archiv : European journal of physiology

2021 Aug 07

Geis, L;Boudriot, FF;Wagner, C;
PMID: 34365513 | DOI: 10.1007/s00424-021-02608-0

Kidneys are thought to express eight different connexin isoforms (i.e., Cx 26, 30, 32, 37, 40, 43, 45, and 46), which form either hemichannels or gap junctions serving to intercellular communication and functional synchronization. Proper function of connexins has already been shown to be crucial for regulation of renal hemodynamics and renin secretion, and there is also growing evidence for connexins to play a role in pathologic conditions such as renal fibrosis or diabetic nephropathy. Therefore, exact intrarenal localization of the different connexin isoforms gains particular interest. Until now intrarenal expression of connexins has mainly been examined by immunohistochemistry, which in part generated conflicting results depending on antibodies and fixation protocols used. In this work, we used fluorescent RNAscope as an alternative technical approach to localize renal connexin mRNAs in healthy mouse kidneys. Addition of RNAscope probes for cell type specific mRNAs was used to assign connexin mRNA signals to specific cell types. We hereby found Cx26 mRNA strongly expressed in proximal tubules, Cx30 mRNA was selectively detected in the urothelium, and Cx32 mRNA was found in proximal tubules and to a lesser extent also in collecting ducts. Cx37 mRNA was mainly associated with vascular endothelium, Cx40 mRNA was largely found in glomerular mesangial and less in vascular endothelial cells, Cx43 mRNA was sparsely expressed by interstitial cells of all kidney zones, and Cx45 mRNA was predominantly found in smooth muscle cell layers of both blood vessels and ureter as well as in mesangial and interstitial (fibroblastic) cells. Cx46 mRNA could not be detected. In summary our results essentially confirm previous data on connexin expression in the renal vasculature and in glomeruli. In addition, they demonstrate strong connexin gene expression in proximal tubules, and they suggest significant connexin expression in resident tubulointerstitial cells.

Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses

JCI insight

2021 Aug 06

Schaller, MA;Sharma, Y;Dupee, Z;Nguyen, DT;Urueña, JM;Smolchek, RA;Loeb, JC;Machuca, TN;Lednicky, JA;Odde, DJ;Campbell, RF;Sawyer, WG;Mehrad, B;
PMID: 34357881 | DOI: 10.1172/jci.insight.148003

Cell lines are the mainstay in understanding the biology of COVID-19 infection, but do not recapitulate many of the complexities of human infection. The use of human lung tissue is one solution for the study of such novel respiratory pathogens. We hypothesized that a cryopreserved bank of human lung tissue allows for the ex vivo study of the inter-individual heterogeneity of host response to SARS-CoV-2 infection, thus providing a bridge between studies with cell lines and studies in animal models. We generated a cryobank of tissues from 21 donors, many of whom had clinical risk factors for severe COVID-19. Cryopreserved tissues preserved 90% cell viability and contained heterogenous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. Samples were readily infectable with HCoV-OC43 and SARS-CoV-2 coronaviruses, and demonstrated comparable susceptibility to infection. In contrast, we observed a marked donor-dependent heterogeneity in the expression of IL6, CXCL8 and IFNB1 in response to SARS-CoV2 infection. Treatment of tissues with dexamethasone and the experimental drug, n-hydroxycytidine, suppressed viral growth in all samples, whereas chloroquine and remdesivir had no detectable effect. Metformin and sirolimus, molecules with predicted but unproven antiviral activity, each suppressed viral replication in tissues from a subset of donors. In summary, we developed a novel system for the ex vivo study of human SARS-CoV- 2 infection using primary human lung tissue from a library of donor tissues. This model may be useful for drug screening and for understanding basic mechanisms of COVID-19 pathogenesis.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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