Clinicopathological and molecular characterization of high-grade endometrial carcinoma with POLE mutation: a single center study

Journal of Gynecologic Oncology

2022 Feb 08

Yu, S;Sun, Z;Zong, L;Yan, J;Yu, M;Chen, J;Lu, Z;
| DOI: 10.3802/jgo.2022.33.e38

Patients with POLEmut generally have early-stage disease [5]; in our study, 93% (40/43) of all POLEmut patients had stage I or II EC, which was consistent with previously reported data [19]. In terms of treatment strategy, our data suggest that the type of adjuvant therapy after surgery does not impact the survival of patients with POLEmut ECs who are FIGO stage I-II disease, which is consistent with the ESGO/ESTRO/ESP clinical practice guidelines [15]; as such, these data maybe support omitting additional adjuvant therapy for such patients, besides, the recent meta-analysis from a 294-patients group also give the similar conclusion [20]. However, FIGO stage III and IV patients with POLEmut are rare [5]; our cohort comprised only 1 patient each with stage III and stage IV (Fig. 1B). The individual with stage III had a very good prognosis (i.e., no recurrence or death 40 months after surgery), but the individual with stage IV had a poor prognosis (Fig. 2, Tables S1 and S2, patient #3). The 2021 ESGO/ESTRO/ESP guidelines define patients with stage III-IV disease with residual tumor as advanced risk, regardless of molecular type [15]. However, no recommendations or instructions are provided for patients with stage III-IVA disease exhibiting POLEmut without residual tumors because of limited data.

Crosstalk Between Pro-Survival Sphingolipid Metabolism and Complement Signaling Induces Inflammasome-Mediated Tumor Metastasis

SSRN Electronic Journal

2022 Feb 17

Janneh, A;Kassir, M;Atilgan, F;Lee, H;Sheridan, M;Oleinik, N;Szulc, Z;Voelkel-Johnson, C;Nguyen, H;Li, H;Peterson, Y;Marangoni, E;Saatci, O;Sahin, O;Lilly, M;Atkinson, C;Tomlinson, S;Mehrotra, S;Ogretmen, B;
| DOI: 10.2139/ssrn.4032074

Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determined how oncogenic sphingosine 1-phosphate (S1P) metabolism activates intracellular C3-complement molecules to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3-complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α′2 was associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α′2 to prevent its association with PPIL1 attenuated inflammasome activation and reduced lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis was highly associated with human metastatic melanoma tissues and patient-derived xenografts (PDXs). Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and/or pharmacologic tools prevented lung colonization/metastasis of B16 melanoma-derived tumors using WT and C3a-receptor1 knockout (C3aR1-/-) mice. Overall, these data provide novel strategies for the treatment of high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.

Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions

Neuron

2022 Jan 12

Yu, H;Miao, W;Ji, E;Huang, S;Jin, S;Zhu, X;Liu, MZ;Sun, YG;Xu, F;Yu, X;
PMID: 35045339 | DOI: 10.1016/j.neuron.2021.12.022

It is well known that affective and pleasant touch promotes individual well-being and facilitates affiliative social communication, although the neural circuit that mediates this process is largely unknown. Here, we show that social-touch-like tactile stimulation (ST) enhances firing of oxytocin neurons in the mouse paraventricular hypothalamus (PVH) and promotes social interactions and positively reinforcing place preference. These results link pleasant somatosensory stimulation to increased social interactions and positive affective valence. We further show that tachykinin 1 (Tac1+) neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) send monosynaptic excitatory projections to PVH oxytocin neurons. Functionally, activation of PVH-projecting Tac1+ neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1+ neurons abolishes ST-induced oxytocin neuronal firing. Together, these results identify a dipeptidergic pathway from l/vlPAG Tac1+ neurons to PVH oxytocin neurons, through which pleasant sensory experience promotes social behavior.

Acute restraint stress redirects prefrontal cortex circuit function through mGlu5 receptor plasticity on somatostatin-expressing interneurons

Neuron

2022 Jan 13

Joffe, ME;Maksymetz, J;Luschinger, JR;Dogra, S;Ferranti, AS;Luessen, DJ;Gallinger, IM;Xiang, Z;Branthwaite, H;Melugin, PR;Williford, KM;Centanni, SW;Shields, BC;Lindsley, CW;Calipari, ES;Siciliano, CA;Niswender, CM;Tadross, MR;Winder, DG;Conn, PJ;
PMID: 35045338 | DOI: 10.1016/j.neuron.2021.12.027

Inhibitory interneurons orchestrate prefrontal cortex (PFC) activity, but we have a limited understanding of the molecular and experience-dependent mechanisms that regulate synaptic plasticity across PFC microcircuits. We discovered that mGlu5 receptor activation facilitates long-term potentiation at synapses from the basolateral amygdala (BLA) onto somatostatin-expressing interneurons (SST-INs) in mice. This plasticity appeared to be recruited during acute restraint stress, which induced intracellular calcium mobilization within SST-INs and rapidly potentiated postsynaptic strength onto SST-INs. Restraint stress and mGlu5 receptor activation each augmented BLA recruitment of SST-IN phasic feedforward inhibition, shunting information from other excitatory inputs, including the mediodorsal thalamus. Finally, studies using cell-type-specific mGlu5 receptor knockout mice revealed that mGlu5 receptor function in SST-expressing cells is necessary for restraint stress-induced changes to PFC physiology and related behaviors. These findings provide new insights into interneuron-specific synaptic plasticity mechanisms and suggest that SST-IN microcircuits may be promising targets for treating stress-induced psychiatric diseases.

Nasopharyngeal cancer: Incidence and prognosis of human papillomavirus and Epstein-Barr virus association at a single North American institution

Head & neck

2022 Jan 18

Wu, SS;Chen, B;Fleming, CW;Shah, AA;Griffith, CC;Domb, C;Reddy, CA;Campbell, SR;Woody, NM;Lamarre, ED;Lorenz, RR;Prendes, BL;Scharpf, J;Schwartzman, L;Geiger, JL;Koyfman, SA;Ku, JA;
PMID: 35040516 | DOI: 10.1002/hed.26976

The prognostication of Epstein-Barr virus (EBV) and human papillomavirus (HPV) status in nasopharyngeal cancer (NPC) is unclear.This retrospective study analyzed NPC from 2000 to 2019.Seventy-eight patients were included: 43 EBV+ , 12 HPV+ , 23 EBV- /HPV- , and 0 EBV+ /HPV+ . All p16+ tumors were also positive for HPV-CISH. Baseline characteristics were not different between groups except age, N-classification, and Karnofsky Performance Scale (KPS) (p < 0.05). For EBV+ , HPV+ , and EBV- /HPV- respectively, 3-year overall survival (OS) was 89.9%, 69.8%, and 52.5% (p = 0.006). EBV- /HPV- status was significantly associated with worse OS but not freedom from progression (FFP) on univariate analysis, and did not remain a significant predictor of OS after adjusting for KPS, age, and group stage.EBV+ NPC tumors were seen in younger, healthier patients than HPV+ and EBV- tumors, and there were no cases of coinfection. The association of viral status with OS was insignificant after adjusting for KPS and age.

The assembly of caprine Y chromosome sequence reveals a unique paternal phylogenetic pattern and improves our understanding of the origin of domestic goat

Ecology and evolution

2021 Jun 01

Xiao, C;Li, J;Xie, T;Chen, J;Zhang, S;Elaksher, SH;Jiang, F;Jiang, Y;Zhang, L;Zhang, W;Xiang, Y;Wu, Z;Zhao, S;Du, X;
PMID: 34188851 | DOI: 10.1002/ece3.7611

The mammalian Y chromosome offers a unique perspective on the male reproduction and paternal evolutionary histories. However, further understanding of the Y chromosome biology for most mammals is hindered by the lack of a Y chromosome assembly. This study presents an integrated in silico strategy for identifying and assembling the goat Y-linked scaffolds using existing data. A total of 11.5 Mb Y-linked sequences were clustered into 33 scaffolds, and 187 protein-coding genes were annotated. We also identified high abundance of repetitive elements. A 5.84 Mb subset was further ordered into an assembly with the evidence from the goat radiation hybrid map (RH map). The existing whole-genome resequencing data of 96 goats (worldwide distribution) were utilized to exploit the paternal relationships among bezoars and domestic goats. Goat paternal lineages were clearly divided into two clades (Y1 and Y2), predating the goat domestication. Demographic history analyses indicated that maternal lineages experienced a bottleneck effect around 2,000 YBP (years before present), after which goats belonging to the A haplogroup spread worldwide from the Near East. As opposed to this, paternal lineages experienced a population decline around the 10,000 YBP. The evidence from the Y chromosome suggests that male goats were not affected by the A haplogroup worldwide transmission, which implies sexually unbalanced contribution to the goat trade and population expansion in post-Neolithic period.

Prediction of RNA subcellular localization: Learning from heterogeneous data sources

iScience

2021 Nov 19

Savulescu, AF;Bouilhol, E;Beaume, N;Nikolski, M;
PMID: 34765919 | DOI: 10.1016/j.isci.2021.103298

RNA subcellular localization has recently emerged as a widespread phenomenon, which may apply to the majority of RNAs. The two main sources of data for characterization of RNA localization are sequence features and microscopy images, such as obtained from single-molecule fluorescent in situ hybridization-based techniques. Although such imaging data are ideal for characterization of RNA distribution, these techniques remain costly, time-consuming, and technically challenging. Given these limitations, imaging data exist only for a limited number of RNAs. We argue that the field of RNA localization would greatly benefit from complementary techniques able to characterize location of RNA. Here we discuss the importance of RNA localization and the current methodology in the field, followed by an introduction on prediction of location of molecules. We then suggest a machine learning approach based on the integration between imaging localization data and sequence-based data to assist in characterization of RNA localization on a transcriptome level.

Developmental programming and lineage branching of early human telencephalon

The EMBO journal

2021 Nov 02

Ma, L;Du, Y;Hui, Y;Li, N;Fan, B;Zhang, X;Li, X;Hong, W;Wu, Z;Zhang, S;Zhou, S;Xu, X;Zhou, Z;Jiang, C;Liu, L;Zhang, X;
PMID: 34558085 | DOI: 10.15252/embj.2020107277

The dorsal and ventral human telencephalons contain different neuronal subtypes, including glutamatergic, GABAergic, and cholinergic neurons, and how these neurons are generated during early development is not well understood. Using scRNA-seq and stringent validations, we reveal here a developmental roadmap for human telencephalic neurons. Both dorsal and ventral telencephalic radial glial cells (RGs) differentiate into neurons via dividing intermediate progenitor cells (IPCs_div) and early postmitotic neuroblasts (eNBs). The transcription factor ASCL1 plays a key role in promoting fate transition from RGs to IPCs_div in both regions. RGs from the regionalized neuroectoderm show heterogeneity, with restricted glutamatergic, GABAergic, and cholinergic differentiation potencies. During neurogenesis, IPCs_div gradually exit the cell cycle and branch into sister eNBs to generate distinct neuronal subtypes. Our findings highlight a general RGs-IPCs_div-eNBs developmental scheme for human telencephalic progenitors and support that the major neuronal fates of human telencephalon are predetermined during dorsoventral regionalization with neuronal diversity being further shaped during neurogenesis and neural circuit integration.

Towards Personalized Medicine: Non-Coding RNAs and Endometrial Cancer

Healthcare (Basel, Switzerland)

2021 Jul 30

Cavaliere, AF;Perelli, F;Zaami, S;Piergentili, R;Mattei, A;Vizzielli, G;Scambia, G;Straface, G;Restaino, S;Signore, F;
PMID: 34442102 | DOI: 10.3390/healthcare9080965

Endometrial cancer (EC) is the most frequent female cancer associated with excellent prognosis if diagnosed at an early stage. The risk factors on which clinical staging is based are constantly updated and genetic and epigenetic characteristics have recently been emerging as prognostic markers. The evidence shows that non-coding RNAs (ncRNAs) play a fundamental role in various biological processes associated with the pathogenesis of EC and many of them also have a prognosis prediction function, of remarkable importance in defining the therapeutic and surveillance path of EC patients. Personalized medicine focuses on the continuous updating of risk factors that are identifiable early during the EC staging to tailor treatments to patients. This review aims to show a summary of the current classification systems and to encourage the integration of various risk factors, introducing the prognostic role of non-coding RNAs, to avoid aggressive therapies where not necessary and to treat and strictly monitor subjects at greater risk of relapse.

Massive Perivillous Fibrin Deposition and Chronic Histiocytic Intervillositis a Complication of SARS-CoV-2 Infection

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society

2021 Jun 03

Marton, T;Hargitai, B;Hunter, K;Pugh, M;Murray, P;
PMID: 34082613 | DOI: 10.1177/10935266211020723

An emerging complication of COVID-19 (SARS-CoV-2) infection is reported. A 23-year-old patient presented with high temperature and reduced fetal movements at 25 + 5/40 weeks of gestation. RT-PCR proved maternal COVID-19 infection. Ultrasound examination confirmed intrauterine death. Placenta histology showed necrosis of the villous trophoblast, associated with Chronic Histiocytic Intervillositis (CHI) and Massive Perivillous Fibrin Deposition (MPFD) with up to 90% - of the intervillous spaces being involved. Immunohistochemistry showed CD68 positive histiocytes in the intervillous spaces and the villous trophoblast was positive for the COVID-19 spike protein. RNA scope signal was indicative of the presence of the viral genome and active viral replication in the villous trophoblastic cells, respectively. MPFD is a gradually developing end-stage disease with various etiology, including autoimmune and alloimmune maternal response to antigens expressed at the feto-maternal interface and frequently accompanies chronic alloimmune villitis or histiocytic intervillositis. Covid-19 infection is associated with similar pattern of histological changes of the placenta leading to placental insufficiency and fetal death. This case report supports maternal- fetal vertical transmission of SARS-CoV-2 virus leading to placental insufficiency and fetal demise. MPFD and CHI appear to be the typical placental histology for SARS-CoV-2 virus infection associated fetal demise.

Thyroid-Like Cholangiocarcinoma: Histopathological, Immunohistochemical, In-Situ Hybridization and Molecular Studies on an Uncommon Emerging Entity

International journal of surgical pathology

2021 May 03

Hissong, E;Chiu, K;Park, H;Solomon, J;Song, W;Jessurun, J;
PMID: 33939475 | DOI: 10.1177/10668969211013906

Thyroid-like cholangiocarcinoma is a very uncommon variant of peripheral-type cholangiocarcinoma. To date, only 4 prior cases have been reported. The molecular features of this tumor have not been described. We report a case of a 60-year-old woman with a tumor that evolved over a period of 10 years. A left hepatectomy specimen showed an 11 cm tumor that on histology exhibited areas reminiscent of a thyroid tumor with follicular and insular features which were positive on immunohistochemistry for cytokeratin 7 and in-situ hybridization for albumin. A detailed molecular analysis failed to show mutations common to cholangiocarcinomas but revealed frameshift mutations in 2 chromatin-remodeling genes, CREBBP and KMNT2A. This case confirms that thyroid-like cholangiocarcinoma is a histologic variant of this tumor that is associated with relatively low growth. As most cholangiocarcinomas, it is diffusely positive for cytokeratin 7 and albumin by in-situ hybridization. Given its rarity, the molecular alterations in this specific histologic subtype remain to be fully elucidated.

Single-cell RNA sequencing to study vascular diversity and function

Current opinion in hematology

2021 May 01

Ma, F;Hernandez, GE;Romay, M;Iruela-Arispe, ML;
PMID: 33714967 | DOI: 10.1097/MOH.0000000000000651

Single-cell RNA sequencing (scRNA-seq) can capture the transcriptional profile of thousands of individual cells concurrently from complex tissues and with remarkable resolution. Either with the goal of seeking information about distinct cell subtypes or responses to a stimulus, the approach has provided robust information and promoted impressive advances in cardiovascular research. The goal of this review is to highlight strategies and approaches to leverage this technology and bypass potential caveats related to evaluation of the vascular cells. As the most recent technological development, details associated with experimental strategies, analysis, and interpretation of scRNA-seq data are still being discussed and scrutinized by investigators across the vascular field. Compilation of this information is valuable for those using the technology but particularly important to those about to start utilizing scRNA-seq to seek transcriptome information of vascular cells. As our field progresses to catalog transcriptomes from distinct vascular beds, it is undeniable that scRNA-seq technology is here to stay. Sharing approaches to improve the quality of cell dissociation procedures, analysis, and a consensus of best practices is critical as information from this powerful experimental platform continues to emerge.

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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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