S4 Segment Research Articles

Lower Urinary Tract Symptoms Should Be Queried When Initiating Sodium Glucose Co-Transporter 2 Inhibitors.

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce the risk of both macrovascular (myocardial infractions and stroke) (1) and microvascular events (progression of CKD) (2) in persons with type 2 diabetes. The beneficial effects of SGLT2i are derived from a cascade of effects subsequent to inhibition of glucose reabsorption in the S1 segment of the proximal tubule. Clinical trials have shown that SGLT2i reduce the absolute risk of kidney failure by 35% (95% CI, 54% to 81%) relative to placebo (2). Thus, SGLT2i may be one of the most important interventions provided for adults at high risk for kidney failure. With any intervention, side effects and adverse effects must be considered to identify patients appropriate for the intervention and to ensure that treated patients are educated regarding potential side effects and the appropriate coping mechanisms for bothersome side effects. For the SGLT2i drug class, adverse events includes hypoglycemia, ketoacidosis, volume depletion (especially when combined with loop diuretics), and genital urinary infections (3⇓⇓–6). Other important side effects that are not life threatening, but are nevertheless bothersome, are lower urinary tract symptoms (LUTS). Below, we describe reasons why LUTS should be queried in patients before initiating SGLT2i and methods for managing LUTS to maintain adherence with this drug class. LUTS include urinary frequency and urgency, with or without incontinence. Urinary urgency, or the sudden urge to urinate that may or may not be accompanied by urinary incontinence, is termed overactive bladder (OAB) syndrome (7). Over 10% of older adults cope with some degree of OAB, and prevalence increases with advancing age (7). Adults with diabetes, especially those with poor glucose control, are particularly at risk for OAB due to bladder dysfunction from neuropathy and osmotic diuresis, which can lead to detrusor muscle hypertrophy and reduction in bladder storage capacity …

Subpleural Lymphatic Permeation in Colorectal Lung Metastases

A 71-year-old woman with a history of rectal cancer 2 years earlier was referred to our department to manage bilateral pulmonary nodules. A chest computed tomography scan showed one lung nodule in the right S1 (13 mm) segment and two nodules in the left S9 (30 mm) and left S10 (10 mm) segments. After resection of the right tumor, a wedge resection was scheduled for the left tumors. However, rosarylike structures were noted beneath the visceral pleura to the hilum (Figures 1A-1C, arrows). We suspected lymphatic invasion; hence, partial resection was considered inappropriate for R0 resection.

The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER.

N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). Functional NMDARs consist of heterotetramers comprised of GluN1, GluN2A-D, and/or GluN3A-B subunits, each of which contains four membrane domains (M1 through M4), an intracellular C-terminal domain, a large extracellular N-terminal domain composed of the amino-terminal domain and the S1 segment of the ligand-binding domain (LBD), and an extracellular loop between M3 and M4, which contains the S2 segment of the LBD. Both the number and type of NMDARs expressed at the cell surface are regulated at several levels, including their translation and posttranslational maturation in the endoplasmic reticulum (ER), intracellular trafficking via the Golgi apparatus, lateral diffusion in the plasma membrane, and internalization and degradation. This review focuses on the roles played by the extracellular regions of GluN subunits in ER processing. Specifically, we discuss the presence of ER retention signals, the integrity of the LBD, and critical N-glycosylated sites and disulfide bridges within the NMDAR subunits, each of these steps must pass quality control in the ER in order to ensure that only correctly assembled NMDARs are released from the ER for subsequent processing and trafficking to the surface. Finally, we discuss the effect of pathogenic missense mutations within the extracellular domains of GluN subunits with respect to ER processing of NMDARs.

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel.

Voltage-gated potassium (KV) channels can be opened by negatively charged resin acids and their derivatives. These resin acids have been proposed to attract the positively charged voltage-sensor helix (S4) toward the extracellular side of the membrane by binding to a pocket located between the lipid-facing extracellular ends of the transmembrane segments S3 and S4. By contrast to this proposed mechanism, neutralization of the top gating charge of the Shaker KV channel increased resin-acid-induced opening, suggesting other mechanisms and sites of action. Here, we explore the binding of two resin-acid derivatives, Wu50 and Wu161, to the activated/open state of the Shaker KV channel by a combination of in silico docking, molecular dynamics simulations, and electrophysiology of mutated channels. We identified three potential resin-acid-binding sites around S4: (1) the S3/S4 site previously suggested, in which positively charged residues introduced at the top of S4 are critical to keep the compound bound, (2) a site in the cleft between S4 and the pore domain (S4/pore site), in which a tryptophan at the top of S6 and the top gating charge of S4 keeps the compound bound, and (3) a site located on the extracellular side of the voltage-sensor domain, in a cleft formed by S1-S4 (the top-VSD site). The multiple binding sites around S4 and the anticipated helical-screw motion of the helix during activation make the effect of resin-acid derivatives on channel function intricate. The propensity of a specific resin acid to activate and open a voltage-gated channel likely depends on its exact binding dynamics and the types of interactions it can form with the protein in a state-specific manner.

Role of tubular epithelial arginase-II in renal inflammaging

The aging kidney undergoes complex changes and is vulnerable to injury and development of chronic kidney disease (CKD) with preponderance affecting more women than men. Evidence has been presented that the type-II L-arginine:ureohydrolase, arginase-II (Arg-II) plays a role in the acceleration of aging. Arg-II is highly expressed in the kidney. However, the role of Arg-II in renal aging is not known. This study is to investigate whether Arg-II is involved in the kidney aging process dependently on sex. Arg-II level in the kidney of wild type (WT) mice is significantly elevated with aging, which is accompanied by an increase in expression of the inflammatory cytokines/chemokines, tissue macrophages, factors involved in fibrosis, and tubulointestitial fibrosis in both males and females. This renal aging phenotype is significantly suppressed in arg-II−/− mice, mainly in the females in which Arg-II level is higher than in the males. Importantly, numerous factors such as IL-1β, MCP1, VCAM-1, and TGFβ1 are mainly localized in the proximal tubular S3 segment cells expressing Arg-II in the aging kidney. In human proximal tubular cells (HK-2), TNF-α enhances adhesion molecule expression dependently on Arg-II upregulation. Overexpression of Arg-II in the cells enhances TGFβ1 levels which is prevented by mitochondrial ROS inhibition. In summary, our study reveals that renal proximal tubular Arg-II plays an important role in the kidney aging process in females. Arg-II could be a promising therapeutic target for the treatment and prevention of aging-associated kidney diseases.

Corridor-diameter-dependent angular tolerance for safe transiliosacral screw placement: an anatomic study of 433 pelves

The purpose of this study was to determine the angular tolerance of the S1 and S2 segments to accommodate a transiliosacral screw across both sacroiliac joints. We hypothesized that the angular tolerance for transiliosacral screw placement would be more constrained than the angular tolerance for iliosacral fixation in pelves where a safe osseous corridor was measured. The cortical boundaries of the S1 and S2 sacral segments in 433 pelvic CTs were digitally mapped. A straight-line path was placed within each osseous corridor and extended across both SI joints past the outer iliac cortices. The diameter of the path was increased until it breached the cortex, geometrically determining maximum diameter (Dmax). Angular tolerance for screw placement was calculated with trigonometric analysis of the Dmax value of the corridor, and the average distance from the termination of the osseous corridor to the site of percutaneous insertion. Gender, age, and BMI were evaluated as independent predictors using binomial logistic regression. The transiliosacral angular tolerance for the S1 and S2 osseous corridors was 1.53 ± 0.57 degrees and 1.02 ± 0.33 degrees, respectively. 68.9% of S1 corridors and 81.1% of S2 corridors had a safe zone (corridor diameter ≥ 10mm) for transiliosacral placement, 48.3% of the pelves had a safe zone for both corridors, while 5.1% had no safe zones. Females had a less frequent Dmax ≥ 10mm at S1, 52% vs 67% (p = 0.001), and at S2, 64% vs 86% (p < 0.001). In conclusion, the angular tolerance of 1.53 and 1.03 degrees for the S1 and S2 segments, respectively, creating a narrow interval for safe passage of the trans-iliac and trans-sacral, with approximately 31.1% of patients not having a viable corridor for screw passage. A correlation exist between S1 and S2 corridors with Dmax ≥ 10mm and the resulting increase in angular tolerance for safe passage of a transilioscral screw. Level Retrospective Cohort.

Laser enucleation of a renal cell carcinoma (RCC) lung metastasis. This video demonstrates a metastasis enucleation using a laser fiber with a power of 60 W. The 64-year-old former heavy smoker male with a history of RCC 18 months prior, was admitted with undefined pulmonary nodules. The procedure started with a uniportal video-assisted thoracic surgery (VATS) wedge resection from segment

Laser enucleation of a renal cell carcinoma (RCC) lung metastasis. This video demonstrates a metastasis enucleation using a laser fiber with a power of 60 W. The 64-year-old former heavy smoker male with a history of RCC 18 months prior, was admitted with undefined pulmonary nodules. The procedure started with a uniportal video-assisted thoracic surgery (VATS) wedge resection from segment

Distribution and imaging characteristics of spina bifida occulta in young people with low back pain: a retrospective cross-sectional study

PurposeSpina bifida occulta (SBO) is one of the most common congenital spinal deformities. Although many studies have demonstrated the influence of lumbosacral dysplasia on low back pain (LBP) in young athletes, there have been few studies on SBO among young people in other occupations. The purpose of this study is to investigate the distribution of SBO in young people with LBP and to classify SBO from the perspective of lamina development.MethodsThe X-ray films of 148 young patients with LBP were analyzed to quantify the distribution of SBO and classify abnormal laminae.ResultsOf the 148 patients, 93 (61.49%) had SBO: 83 cases involved S1 alone, 2 involved L5–S1, 5 involved S1–2, 2 involved S1–4, and 1 involved L4–S4. According to the degree of the defect, the patients with SBO were divided on the basis of five grades: 9 patients with grade I, 53 with grade II, 23 with grade III, and 8 with grade IV. The cases were classified by the shape of the laminae into 4 types: 15 cases of type a, 11 cases of type b, 37 cases of type c, and 30 cases of type d.ConclusionAmong the young people with LBP that we surveyed, SBO is the most common lumbosacral dysplasia, which frequently involves the S1 segment. Most laminae in SBO are in the developmental stage of the spinous process, and an abnormal laminar growth direction and laminar stenosis are the most common laminar morphologies in SBO.

Single-Cell Imaging for Studies of Renal Uranium Transport and Intracellular Behavior

Nephrotoxicity is the primary health effect of uranium exposure. However, the renal transport and intracellular behavior of uranium remains to be clearly elucidated. In the present study, the intracellular uranium distribution was examined with the cell lines derived from the S3 segment of mouse renal proximal tubules, which is a toxic target site of uranium, using microbeam-based elemental analysis. Uranium exposure at 100 μM for 24 h (non-toxic phase) was performed in S3 cells. Two types of measurement specimens, including those that are adhesive cell specimens and cryosection specimens, were examined for the positional relationship of the intracellular localization of uranium. Based on the combined results of single-cell imaging from the two types of cell specimens, uranium was distributed inside the cell and localized in the cytoplasm near the cell nucleus. In some cells, uranium was colocalized with phosphorus and potassium. The amount of uranium accumulated in S3 cells was estimated using thin section-standards. The mean uranium content of three adhesive cells was hundreds of femtogram per cell. Thus, we believe that single-cell imaging would be useful for studies on renal uranium transportation and cellular behavior.

The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

CACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

Disease-Related TRPM3 Mutations Render the Channel Overactive via Different Mechanisms

The Transient Receptor Potential Melastatin 3 (TRPM3) ion channelis a calcium permeable non-selective ion channel and it belongs to the Transient Receptor Potential (TRP) superfamily. TRPM3 has been identified as a thermosensitive nociceptor channel which can be activated by noxious heat. TRPM3 knockout mice show impairment in avoiding noxious heat and have defects in developing inflammatory heat hyperalgesia. TRPM3 can also be activated by chemical agonists such as pregnenolone sulfate (PregS), CIM0216 and clotrimazole.The presence of de novo substitutions of TRPM3 has been reported in human pediatric patients with intellectual disability and epilepsy recently. Either the Val 990 (992) Met or the Pro 1090 (1092) Gln was found in those patients, however the functional effects of those mutations were not reported. We find that both mutations make the channel overactive increasing basal activity, as well as increasing sensitivity to agonist and heat. The TRPM3-Val990Met mutant shows higher basal activity and it makes the channel more sensitive towards different agonists such as PregS and CIM0216 than the Pro1090Gln mutant. The Val to Mel substitution is located in the S4-S5 loop which could help to understand the increased sensitivity of mutated TRPM3 towards different agonists since the S4-S5 loop is the hot spots for ligand binding in many TRP channels. In contrast, the extracellular S6 segment mutation, Pro1090Gln, increases the sensitivity of TRPM3 towards heat activation to a larger extent than the Val990Met mutation. Both mutated TRPM3 channels can be inhibited by primidone, which is a clinically approved anti-epileptic drug, suggesting the potential treatment of this type of disease.

A Second S4 Movement Opens Hyperpolarization-Activated HCN Channels

Rhythmic activity in pacemaker cells, such as in sino-atrial node cardiomyocytes, depends on the activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. As in depolarization-activated K+ channels, the fourth transmembrane segment S4 is positively charged and functions as the voltage sensor in hyperpolarization-activated HCN channels. But how the inward movement of S4 at negative voltages couples to channel opening in HCN channels is not understood. In the cryo-EM structure of the human HCN1 channel with S4 in the up/resting state and the gate closed, there is an interaction between a glutamate in S4 and an asparagine in S5. We measured the effects of mutations of the homologous residues (E356 and N370) in the sea urchin HCN channel on S4 and gate movements using Voltage Clamp Fluorometry. Our results show that a hydrogen bond between E356 and N370 stabilizes S4 in its up state. Breaking this hydrogen bond by inserting the E356A mutation shifts the main S4 movement to positive voltages, but channel opening remains at negative voltages. Instead, E356A reveals a second S4 movement at negative voltages that correlates with gate opening. Our data suggest a model in which a hydrogen bond between S4 and S5 stabilizes S4 in the up/resting state. Upon hyperpolarization, this bond is broken by the initial inward S4 movement, whereas a subsequent S4 movement triggers channel opening. Our molecular models suggest that the second S4 movement opens a hydrophilic intracellular crevice between S4 and S5 that would allow radial movement of the intracellular ends of S5 and S6 to open the pore of HCN channels.

A multitarget semi-synthetic derivative of the flavonoid morin with improved in vitro vasorelaxant activity: Role of CaV1.2 and KCa1.1 channels

CaV1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca2+ antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on CaV1.2 and KCa1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective CaV1.2 channel blockers, positioning in the α1C subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca2+ antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca2+ from the sarcoplasmic reticulum; surprisingly, it also stimulated KCa1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the KCa1.1 channel S6 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension.

Protein structural heterogeneity: A hypothesis for the basis of proteolytic recognition by the main protease of SARS-CoV and SARS-CoV-2

The main protease (Mpro) of SARS-CoV and SARS-CoV-2 is a key enzyme in viral replication and a promising target for the development of antiviral therapeutics. The understanding of this protein is based on a number of observations derived from earlier x-ray structures, which mostly consider substrates or ligands as the main reason behind modulation of the active site. This lead to the concept of substrate-induced subsite cooperativity as an initial attempt to explain the dual binding specificity of this enzyme in recognizing the cleavage sequences at its N- and C-termini, which are important processing steps in obtaining the mature protease. The presented hypothesis proposes that structural heterogeneity is a property of the enzyme, independent of the presence of a substrate or ligand. Indeed, the analysis of Mpro structures of SARS-CoV and SARS-CoV-2 reveals a conformational diversity for the catalytically competent state in ligand-free structures. Variation in the binding site appears to result from flexibility at residues lining the S1 subpocket and segments incorporating methionine 49 and glutamine 189. The structural evidence introduces “structure-based recognition” as a new paradigm in substrate proteolysis by Mpro. In this concept, the binding space in subpockets of the enzyme varies in a non-cooperative manner, causing distinct conformations, which recognize and process different cleavage sites, as the N- and C-termini. Insights into the recognition basis of the protease provide explanation to the ordered processing of cleavage sites. The hypothesis expands the conformational space of the enzyme and consequently opportunities for drug development and repurposing efforts.

Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel.

The KCNA1 gene encodes the α subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2–S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation.

Recombinant Baculovirus-Produced Grass Carp Reovirus Virus-Like Particles as Vaccine Candidate That Provides Protective Immunity against GCRV Genotype II Infection in Grass Carp.

Grass carp reovirus (GCRV) leads to severe hemorrhagic disease in grass carp (Ctenopharyngodon idella) and causes economic losses in grass carp aquaculture. Recent epidemiological investigations showed that GCRV genotype II is the dominant subtype in China. Therefore, it is very important to develop a novel vaccine for preventing diseases caused by GCRV genotype II. In this study, we employed a bac-to-bac expression system to generate GCRV-II-based virus-like particles (VLPs). Previous studies have shown that the structural proteins VP3, VP4, and VP38 encoded by the segments S3, S6, and S10 of type II GCRV are immunogenic. Hence, the GCRV-VLPs were produced by co-infection of sf9 cells with recombinant baculoviruses PFBH-VP3, PFBH-VP4, and PFBH-VP38. The expressions of VP3, VP4, and VP38 proteins in GCRV-VLPs were tested by IFA and Western blot analysis. By electron microscopic observations of ultrathin sections, purified VLPs showed that the expressed proteins are similar in shape to GCRV genotype II with a size range from 40 nm to 60 nm. The immunogenicity of GCRV-VLPs was evaluated by the injection immunization of grass carp. The analysis of serum-specific IgM antibody showed that grass carp immunized with GCRV-VLPs produced GCRV-specific antibodies. Furthermore, injection with GCRV-VLPs increased the expressions of immune-related genes (IgM, IFN, TLR3, TLR7) in the spleen and kidney. In addition, grass carp immunized with a GCRV-VLPs-based vaccine showed a relative percent survival rate (RPS) of 83.33% after challenge. The data in this study showed that GCRV-VLPs demonstrated an excellent immunogenicity and represent a promising approach for vaccine development against GCRV genotype II infection.

Extensive Phylogenetic Analysis of Piscine Orthoreovirus Genomic Sequences Shows the Robustness of Subgenotype Classification.

Piscine orthoreovirus (PRV) belongs to the family Reoviridae and has been described mainly in association with salmonid infections. The genome of PRV consists of about 23,600 bp, with 10 segments of double-stranded RNA, classified as small (S1 to S4), medium (M1, M2 and M3) and large (L1, L2 and L3); these range approximately from 1000 bp (segment S4) to 4000 bp (segment L1). How the genetic variation among PRV strains affects the virulence for salmonids is still poorly understood. The aim of this study was to describe the molecular phylogeny of PRV based on an extensive sequence analysis of the S1 and M2 segments of PRV available in the GenBank database to date (May 2020). The analysis was extended to include new PRV sequences for S1 and M2 segments. In addition, subgenotype classifications were assigned to previously published unclassified sequences. It was concluded that the phylogenetic trees are consistent with the original classification using the PRV genomic segment S1, which differentiates PRV into two major genotypes, I and II, and each of these into two subgenotypes, designated as Ia and Ib, and IIa and IIb, respectively. Moreover, some clusters of country- and host-specific PRV subgenotypes were observed in the subset of sequences used. This work strengthens the subgenotype classification of PRV based on the S1 segment and can be used to enhance research on the virulence of PRV.

Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin

Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50 = 11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels.

Isolation and characterization of novel reassortant mammalian orthoreovirus from pigs in the United States

Mammalian orthoreovirus (MRV) infects multiple mammalian species including humans. A United States Midwest swine farm with approximately one thousand 3-month-old pigs experienced an event, in which more than 300 pigs showed neurological signs, like “down and peddling”, with approximately 40% mortality. A novel MRV was isolated from the diseased pigs. Sequence and phylogenetic analysis revealed that the isolate was a reassortant virus containing viral gene segments from three MRV serotypes that infect human, bovine and swine. The M2 and S1 segment of the isolate showed 94% and 92% nucleotide similarity to the M2 of the MRV2 D5/Jones and the S1 of the MRV1 C/bovine/Indiana/MRV00304/2014, respectively; the remaining eight segments displayed 93%-94% nucleotide similarity to those of the MRV3 FS-03/Porcine/USA/2014. Pig studies showed that both MRV-infected and native contact pigs displayed fever, diarrhea and nasal discharge. MRV RNA was detected in different intestinal locations of both infected and contact pigs, indicating that the MRV isolate is pathogenic and transmissible in pigs. Seroconversion was also observed in experimentally infected pigs. A prevalence study on more than 180 swine serum samples collected from two states without disease revealed 40-52% positive to MRV. All results warrant the necessity to monitor MRV epidemiology and reassortment as the MRV could be an important pathogen for the swine industry and a novel MRV might emerge to threaten animal and public health.

Surgical treatment of Epstein-Barr virus–associated lymphoepithelioma-like carcinoma occurring in both the posterior mediastinum and liver

Rationale:Lymphoepithelioma-like carcinoma (LELC) is a rare malignant tumor that can occur in many areas of the body. The pathogenesis of LELC remains unknown, but Epstein-Barr virus (EBV) has been shown to be strongly correlated with LELC at several anatomic sites, including the lungs and thymus. To the best of our knowledge, EBV-associated LELC has never been reported in both the posterior mediastinum and liver. Herein, we report the case of a 41-year-old female diagnosed with LELC in both the posterior mediastinum and liver and discuss whether it is beneficial to perform surgery on advanced LELC when resectable metastases are found.Patient concerns:The patient was a 41-year-old woman who had been suffering from intermittent pain in the upper right quadrant for 3 months without obvious cause and was admitted to our hospital with occasional nausea without vomiting.Diagnosis:Her cancer antigen 125 and cytokeratin 19 fragment levels were elevated, whereas alpha-fetoprotein and alanine aminotransferase were normal. Computed tomography (CT) and magnetic resonance imaging revealed a mass in the S6 segment of the liver. Whole-body positron emission tomography/computed tomography (PET/CT) revealed a 3.2-cm mass in the posterior mediastinum and a 6.7-cm mass on the right side of the liver. We made a diagnosis of LELC based on the histological and immunohistochemical findings of specimens obtained by operation. However, it was difficult to determine the primary origin of the tumor.Interventions:The patient underwent mediastinal tumor resection, hepatectomy, and diaphragmatic repair. Thereafter, she was administered paclitaxel and cisplatin as adjuvant chemotherapy.Outcomes:The postoperative course was uneventful, and the patient was discharged 10 days later. Although she was administered paclitaxel and cisplatin as adjuvant chemotherapy, we noted recurrence during the 4-month follow-up examination. Then, the patient passed away 5 months after surgery.Lessons:We present the first case of LELC found in both the posterior mediastinum and liver and describe the functionality of PET/CT for finding occult carcinomas and identifying their primary tumor origin. Additional studies are urgently needed to discover whether it is beneficial to perform surgery on advanced LELC when resectable metastases are revealed by PET/CT.