Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

PloS one

2021 Feb 17

Milani, V;Zara, ALSA;da Silva, EN;Cardoso, LB;Curado, MP;Ribeiro-Rotta, RF;
PMID: 33596233 | DOI: 10.1371/journal.pone.0246475

The efficiency of public policies includes the measurement of the health resources used and their associated costs. There is a lack of studies evaluating the economic impact of oral cancer (OC). This study aims to estimate the healthcare costs of OC in Brazil from 2008 to 2016. This is a partial economic evaluation using the gross costing top-down method, considering the direct healthcare costs related to outpatients, inpatients, intensive care units, and the number of procedures, from the perspective of the public health sector. The data were extracted from the Outpatient and Inpatient Information System of the National Health System, by diagnosis according to the 10th Revision of the International Classification of Diseases, according to sites of interest: C00 to C06, C09 and C10. The values were adjusted for annual accumulated inflation and expressed in 2018 I$ (1 I$ = R$2,044). Expenditure on OC healthcare in Brazil was I$495.6 million, which was composed of 50.8% (I$251.6 million) outpatient and 49.2% (I$244.0 million) inpatient healthcare. About 177,317 admissions and 6,224,236 outpatient procedures were registered. Chemotherapy and radiotherapy comprised the largest number of procedures (88.8%) and costs (94.9%). Most of the costs were spent on people over 50 years old (72.9%) and on males (75.6%). Direct healthcare costs in Brazil for OC are substantial. Outpatient procedures were responsible for the highest total cost; however, inpatient procedures had a higher cost per procedure. Men over 50 years old consumed most of the cost and procedures for OC. The oropharynx and tongue were the sites with the highest expenditure. Further studies are needed to investigate the cost per individual, as well as direct non-medical and indirect costs of OC.

Therapeutic shutdown of HBV transcripts promotes reappearance of the SMC5/6 complex and silencing of the viral genome in vivo

Gut

2021 Jan 28

Allweiss, L;Giersch, K;Pirosu, A;Volz, T;Muench, RC;Beran, RK;Urban, S;Javanbakht, H;Fletcher, SP;Lütgehetmann, M;Dandri, M;
PMID: 33509930 | DOI: 10.1136/gutjnl-2020-322571

Silencing of the therapeutic strategies and reducing the HBV reservoir, the covalently closed circular DNA (cccDNA), have the potential to cure chronic HBV infection. We aimed to investigate the impact of small interferring RNA (siRNA) targeting all HBV transcripts or pegylated interferon-α (peg-IFNα) on the viral regulatory HBx protein and the structural maintenance of chromosome 5/6 complex (SMC5/6), a host factor suppressing cccDNA transcription. In particular, we assessed whether interventions lowering HBV transcripts can achieve and maintain silencing of cccDNA transcription in vivo. HBV-infected human liver chimeric mice were treated with siRNA or peg-IFNα. Virological and host changes were analysed at the end of treatment and during the rebound phase by qualitative PCR, ELISA, immunoblotting and chromatin immunoprecipitation. RNA in situ hybridisation was combined with immunofluorescence to detect SMC6 and HBV RNAs at single cell level. The entry inhibitor myrcludex-B was used during the rebound phase to avoid new infection events. Both siRNA and peg-IFNα strongly reduced all HBV markers, including HBx levels, thus enabling the reappearance of SMC5/6 in hepatocytes that achieved HBV-RNA negativisation and SMC5/6 association with the cccDNA. Only IFN reduced cccDNA loads and enhanced IFN-stimulated genes. However, the antiviral effects did not persist off treatment and SMC5/6 was again degraded. Remarkably, the blockade of viral entry that started at the end of treatment hindered renewed degradation of SMC5/6. These results reveal that therapeutics abrogating all HBV transcripts including HBx promote epigenetic suppression of the HBV minichromosome, whereas strategies protecting the human hepatocytes from reinfection are needed to maintain cccDNA silencing.

Single-cell RNA sequencing reveals SARS-CoV-2 infection dynamics in lungs of African green monkeys

Science translational medicine

2021 Jan 27

Speranza, E;Williamson, BN;Feldmann, F;Sturdevant, GL;Pérez-Pérez, L;Meade-White, K;Smith, BJ;Lovaglio, J;Martens, C;Munster, VJ;Okumura, A;Shaia, C;Feldmann, H;Best, SM;de Wit, E;
PMID: 33431511 | DOI: 10.1126/scitranslmed.abe8146

Detailed knowledge about the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is important for uncovering the viral and host factors that contribute to coronavirus disease 2019 (COVID-19) pathogenesis. Old-World nonhuman primates recapitulate mild to moderate cases of COVID-19, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with infectious SARS-CoV-2 or irradiated, inactivated virus to study the dynamics of virus replication throughout the respiratory tract. Genomic RNA from the animals inoculated with the irradiated virus was found to be highly stable, whereas subgenomic RNA, an indicator of viral replication, was found to degrade quickly. We combined this information with single-cell RNA sequencing of cells isolated from the lung and lung-draining mediastinal lymph nodes and developed new analysis methods for unbiased targeting of important cells in the host response to SARS-CoV-2 infection. Through detection of reads to the viral genome, we were able to determine that replication of the virus in the lungs appeared to occur mainly in pneumocytes, whereas macrophages drove the inflammatory response. Monocyte-derived macrophages recruited to the lungs, rather than tissue-resident alveolar macrophages, were most likely to be responsible for phagocytosis of infected cells and cellular debris early in infection, with their roles switching during clearance of infection. Together, our dataset provides a detailed view of the dynamics of virus replication and host responses over the course of mild COVID-19 and serves as a valuable resource to identify therapeutic targets.

Development And Validation Of Painface, A Software Platform That Simplifies And Standardizes Mouse Grimace Analyses

The Journal of Pain

2023 Apr 01

Zylka, M;McCoy, E;Park, S;Patel, R;Ryan, D;Mullen, Z;Nesbitt, J;Lopez, J;Taylor-Blake, B;Krantz, J;Hu, W;Garris, R;Lima, L;Sotocinal, S;Austin, J;Kashlan, A;Jimenez, J;Shah, S;Trocinski, A;Vanden, K;Major, R;Bazick, H;Klein, M;Mogil, J;Wu, G;
| DOI: 10.1016/j.jpain.2023.02.113

Facial grimaces are now commonly used to quantify spontaneous pain in mice and other mammalian species, but scoring remains subjective and relies on humans with very different levels of proficiency. Here, we developed a Mouse Grimace Scale (MGS) for black-coated (C57BL/6) mice consisting of four facial action units (orbitals, nose, ears, whiskers). We used this scale to generate ground truth data from over 70,000 images of black mice in different settings. With this large data set, we developed a deep neural network and cloud-based software platform called PainFace (http://painface.net) that accurately scores facial grimaces of black mice on a 0-8 scale. PainFace generates over two orders of magnitude more MGS data than humans can realistically achieve, and at superhuman speed. By analyzing the frequency distribution of grimace scores, we found that mice spent >7x more time in a high grimace state following laparotomy surgery relative to sham surgery controls. The analgesic carprofen reduced the amount of time animals spent in this high grimace state after surgery. Specific facial action unit score combinations were overrepresented following laparotomy surgery, suggesting that characteristic facial expressions are associated with a high grimace state. While this study is focused on mice, PainFace was designed to simplify, standardize, and scale up grimace analyses with many other mammalian species, including humans. This work was supported by a grant from the NINDS (R01NS114259) to M.J.Z. NSF GRFP awarded to R.P.P.

Exploring Corticospinal Functional Connectome Using Resting-State Functional Magnetic Resonance Imaging

The Journal of Pain

2023 Apr 01

Kaptan, M;Law, C;Weber, K;Pfyffer, D;Zhang, X;Maronesy, T;Glover, G;Mackey, S;
| DOI: 10.1016/j.jpain.2023.02.065

Investigation of spontaneous- so-called‘resting-state'-activity of the central nervous system with functional magnetic resonance imaging (fMRI) holds great clinical potential to identify possible prognostic and diagnostic biomarkers for pain disorders and provides novel insights into the functional architecture of the central nervous system. Although previous resting-state studies in humans characterized functional networks of the brain and recently of the spinal cord, the resting-state networks of the entire central nervous system-delineating the interaction between the cord and the brain-have not been well characterized, possibly due to technical difficulties of corticospinal fMRI. Given the important role of ascending and descending pathways to understand disorders chronic pain disorders, here we characterize the resting-state functional connectivity networks along the whole neuroaxis in 29 healthy humans as a step prior to clinical studies. 31 brain slices and 12 cervical spinal cord slices from were acquired with a tailored fMRI sequence on a 3T system. Time courses of dorsal and ventral horns were used to map spinal cord's connection to the brain via a seed-based approach. Functional connectivity maps revealed that dorsal and ventral horn are significantly correlated with sensory and motor areas in the brain such as primary and somatosensory and motor cortices as well as with the thalamus. At the same time, we have observed that they somewhat distinct functional connectivity profiles in line with their functional segregation; frontal, occipital and insular cortices were more synchronized with ventral horn whereas caudate and thalamus appeared to be more synchronized with dorsal horn reflecting their functional division. NIH NINDS R01 NS109450.

The Protective Effect of Social Reward on Opioid and Psychostimulant Reward and Relapse: Behavior, Pharmacology, and Brain Regions

The Journal of neuroscience : the official journal of the Society for Neuroscience

2022 Dec 14

Venniro, M;Marino, RAM;Chow, JJ;Caprioli, D;Epstein, DH;Ramsey, LA;Shaham, Y;
PMID: 36517252 | DOI: 10.1523/JNEUROSCI.0931-22.2022

Until recently, most modern neuroscience research on addiction using animal models did not incorporate manipulations of social factors. Social factors play a critical role in human addiction: social isolation and exclusion can promote drug use and relapse, while social connections and inclusion tend to be protective. Here, we discuss the state of the literature on social factors in animal models of opioid and psychostimulant preference, self-administration, and relapse. We first summarize results from rodent studies on behavioral, pharmacological, and circuit mechanisms of the protective effect of traditional experimenter-controlled social interaction procedures on opioid and psychostimulant conditioned place preference, self-administration, and relapse. Next, we summarize behavioral and brain-mechanism results from studies using newer operant social-interaction procedures that inhibit opioid and psychostimulant self-administration and relapse. We conclude by discussing how the reviewed studies point to future directions for the addiction field and other neuroscience and psychiatric fields, and their implications for mechanistic understanding of addiction and development of new treatments.SIGNIFICANCE STATEMENT In this review, we propose that incorporating social factors into modern neuroscience research on addiction could improve mechanistic accounts of addiction and help close gaps in translating discovery to treatment. We first summarize rodent studies on behavioral, pharmacological, and circuit mechanisms of the protective effect of both traditional experimenter-controlled and newer operant social-interaction procedures. We then discuss potential future directions and clinical implications.

Female Urethral Carcinoma: A contemporary review of the clinicopathologic features, with emphasis on the histo-anatomic landmarks and potential staging issues

Human pathology

2022 Aug 26

Lagarde-Lenon, MS;Aron, M;
PMID: 36037997 | DOI: 10.1016/j.humpath.2022.08.003

Primary female urethral carcinoma (PUC-F) accounts for less than 1% of all genitourinary malignancies and comprises a histologically diverse group of tumors that are usually associated with poor prognosis. The carcinomas documented at this site include adenocarcinoma (clear cell adenocarcinoma, columnar cell carcinoma and Skene gland adenocarcinoma), urothelial carcinoma (UCa) and squamous cell carcinoma (SCC). Recent studies have shown adenocarcinomas to be the most common type of primary urethral carcinoma in females. Since most of the urethral carcinomas morphologically resemble carcinomas arising from surrounding pelvic organs or metastases, these should be ruled out before making the diagnosis of PUC-F. These tumors are currently staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. However, the AJCC system has limitations, including the staging of tumors involving the anterior wall of the urethra. Staging systems like the recently proposed histology based female urethral carcinoma staging system (UCS) takes into account the unique histological landmarks of the female urethra to better stratify pT2 and pT3 tumors into prognostic groups, that correlate with clinical outcomes including recurrence rates, disease-specific and overall survival. Further larger multi-institutional cohorts are however required to validate the results of this staging system. There is very limited information regarding the molecular profiling of PUC-F. 31% of clear cell adenocarcinomas have been reported to show PIK3CA alterations, while 15% of adenocarcinomas show PTEN mutations. Higher tumor mutational burden (TMB) and PD-L1 staining have been reported in UCa and SCC. Although multimodality treatment is usually recommended in locally advanced and metastatic disease, the role of immunotherapy and targeted therapy is promising in select PUC-F cases.

Myeloid cell tropism enables MHC-E-restricted CD8+ T cell priming and vaccine efficacy by the RhCMV/SIV vaccine

Science immunology

2022 Jun 24

Hansen, SG;Hancock, MH;Malouli, D;Marshall, EE;Hughes, CM;Randall, KT;Morrow, D;Ford, JC;Gilbride, RM;Selseth, AN;Trethewy, RE;Bishop, LM;Oswald, K;Shoemaker, R;Berkemeier, B;Bosche, WJ;Hull, M;Silipino, L;Nekorchuk, M;Busman-Sahay, K;Estes, JD;Axthelm, MK;Smedley, J;Shao, D;Edlefsen, PT;Lifson, JD;Früh, K;Nelson, JA;Picker, LJ;
PMID: 35714200 | DOI: 10.1126/sciimmunol.abn9301

The strain 68-1 rhesus cytomegalovirus (RhCMV)-based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8+ T cells that recognize epitopes presented by major histocompatibility complex (MHC)-II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II- and/or MHC-Ia-restricted CD8+ T cells do not protect against SIV, it remains unclear whether MHC-E-restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II-restricted component. Using host microRNA (miR)-mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope-targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142-mediated tropism restriction eliminated MHC-E epitope-targeted CD8+ T cell priming, yielding an exclusively MHC-II epitope-targeted response. Inhibition with the endothelial cell-selective miR-126 eliminated MHC-II epitope-targeted CD8+ T cell priming, yielding an exclusively MHC-E epitope-targeted response. Dual miR-142 + miR-126-mediated tropism restriction reverted CD8+ T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8+ T cell responses were generally similar, only the vectors programmed to elicit MHC-E-restricted CD8+ T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.

The multifaceted melanocortin receptors

Endocrinology

2022 Jun 14

Laiho, L;Murray, JF;
PMID: 35700124 | DOI: 10.1210/endocr/bqac083

The five known melanocortin receptors (MCs) have established physiological roles. With the exception of MC2, these receptors can behave unpredictably and since they are more widely expressed than their established roles would suggest, it is likely that they have other poorly characterized functions. The aim of this review is to discuss some of the less well-explored aspects of the four enigmatic members of this receptor family (MC1,3-5) and describe how these are multifaceted G-protein coupled receptors (GPCRs). These receptors appear to be promiscuous in that they bind several endogenous agonists (products of the proopiomelanocortin gene) and antagonists but with inconsistent relative affinities and effects. We propose that this is a result of post-translational modifications that determine receptor localization within nanodomains. Within each nanodomain there will be a variety of proteins, including ion channels, modifying proteins and other GPCRs,that can interact with the MCs to alter the availability of receptor at the cell surface as well as the intracellular signalling resulting from receptor activation. Different combinations of interacting proteins and MCs may therefore give rise to the complex and inconsistent functional profiles reported for the MCs. For further progress in understanding this family, improved characterization of tissue-specific functions is required. Current evidence for interactions of these receptors with a range of partners resulting in modulation of cell signalling suggests that each should be studied within the full context of their interacting partners. The role of physiological status in determining this context also remains to be characterized.

Transcriptome and unique cytokine microenvironment of Castleman disease

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2021 Oct 22

Wing, A;Xu, J;Meng, W;Rosenfeld, AM;Li, EY;Wertheim, G;Paessler, M;Bagg, A;Frank, D;Tan, K;Teachey, DT;Lim, MS;Prak, EL;Fajgenbaum, DC;Pillai, V;
PMID: 34686774 | DOI: 10.1038/s41379-021-00950-3

Castleman disease (CD) represents a group of rare, heterogeneous and poorly understood disorders that share characteristic histopathological features. Unicentric CD (UCD) typically involves a single enlarged lymph node whereas multicentric CD (MCD) involves multiple lymph node stations. To understand the cellular basis of CD, we undertook a multi-platform analysis using targeted RNA sequencing, RNA in-situ hybridization (ISH), and adaptive immune receptor rearrangements (AIRR) profiling of archived tissue from 26 UCD, 14 MCD, and 31 non-CD reactive controls. UCD showed differential expression and upregulation of follicular dendritic cell markers (CXCL13, clusterin), angiogenesis factors (LPL, DLL4), extracellular matrix remodeling factors (TGFβ, SKIL, LOXL1, IL-1β, ADAM33, CLEC4A), complement components (C3, CR2) and germinal center activation markers (ZDHHC2 and BLK) compared to controls. MCD showed upregulation of IL-6 (IL-6ST, OSMR and LIFR), IL-2, plasma cell differentiation (XBP1), FDC marker (CXCL13, clusterin), fibroblastic reticular cell cytokine (CCL21), angiogenesis factor (VEGF), and mTORC1 pathway genes compared to UCD and controls. ISH studies demonstrated that VEGF was increased in the follicular dendritic cell-predominant atretic follicles and the interfollicular macrophages of MCD compared to UCD and controls. IL-6 expression was higher along interfollicular vasculature-associated cells of MCD. Immune repertoire analysis revealed oligoclonal expansions of T-cell populations in MCD cases (2/6) and UCD cases (1/9) that are consistent with antigen-driven T cell activation. The findings highlight the unique genes, pathways and cell types involved in UCD and MCD. We identify potential novel targets in CD that may be harnessed for therapeutics.

The wheat stem rust (Puccinia graminis f. sp. tritici) population from Washington contains the most virulent isolates reported on barley

Plant disease

2021 Sep 21

Upadhaya, A;Gc Upadhaya, S;Brueggeman, RS;
PMID: 34546770 | DOI: 10.1094/PDIS-06-21-1195-RE

A diverse sexual population of wheat stem rust, Puccinia graminis f. sp. tritici (Pgt), exist in the Pacific Northwest (PNW) region of the United States due to the natural presence of Mahonia spp. that serve as alternate hosts to complete its sexual life cycle. The region appears to be a center of stem rust diversity in North America where novel virulence gene combinations can emerge that could overcome deployed barley and wheat stem rust resistances. A total of 100 single pustule isolates derived from stem rust samples collected from barley in Eastern Washington during the 2019 growing season were assayed for virulence on the two known effective barley stem rust resistance genes/loci, Rpg1 and the rpg4/5-mediated resistance locus (RMRL) at the seedling stage. Interestingly, 99% of the Pgt isolates assayed were virulent on barley variety Morex carrying the Rpg1 gene, and 62% of the isolates were virulent on the variety Golden Promise transformant (H228.2c) that carries a single copy insertion of the Rpg1 gene from Morex and is more resistant than Morex to many Rpg1 avirulent isolates. Also, 16% of the isolates were virulent on the near isogenic line HQ-1, that carries the RMRL introgression from the barley line Q21861 in the susceptible Harrington background. Alarmingly, 10% of the isolates were virulent on barley line Q21861 that contains both Rpg1 and RMRL. Thus, we report on the first Pgt isolates worldwide with virulence on both Rpg1 and RMRL when stacked together representing the most virulent Pgt isolates reported on barley.

Intrinsic and growth-mediated cell and matrix specialization during murine meniscus tissue assembly

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2021 Aug 01

Tsinman, TK;Jiang, X;Han, L;Koyama, E;Mauck, RL;Dyment, NA;
PMID: 34314047 | DOI: 10.1096/fj.202100499R

The incredible mechanical strength and durability of mature fibrous tissues and their extremely limited turnover and regenerative capacity underscores the importance of proper matrix assembly during early postnatal growth. In tissues with composite extracellular matrix (ECM) structures, such as the adult knee meniscus, fibrous (Collagen-I rich), and cartilaginous (Collagen-II, proteoglycan-rich) matrix components are regionally segregated to the outer and inner portions of the tissue, respectively. While this spatial variation in composition is appreciated to be functionally important for resisting complex mechanical loads associated with gait, the establishment of these specialized zones is poorly understood. To address this issue, the following study tracked the growth of the murine meniscus from its embryonic formation through its first month of growth, encompassing the critical time-window during which animals begin to ambulate and weight bear. Using histological analysis, region specific high-throughput qPCR, and Col-1, and Col-2 fluorescent reporter mice, we found that matrix and cellular features defining specific tissue zones were already present at birth, before continuous weight-bearing had occurred. These differences in meniscus zones were further refined with postnatal growth and maturation, resulting in specialization of mature tissue regions. Taken together, this work establishes a detailed timeline of the concurrent spatiotemporal changes that occur at both the cellular and matrix level throughout meniscus maturation. The findings of this study provide a framework for investigating the reciprocal feedback between cells and their evolving microenvironments during assembly of a mechanically robust fibrocartilage tissue, thus providing insight into mechanisms of tissue degeneration and effective regenerative strategies.

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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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