Herpes simplex virus 1 (HSV-1) capsids leave the nucleus by a process of envelopment and de-envelopment at the nuclear envelope (NE) that is accompanied by structural alterations of the NE. As capsids translocate across the NE, transient primary enveloped virions form in the perinuclear space. Here, we provide evidence that torsinA (TA), a ubiquitously expressed ATPase, has a role in HSV-1 nuclear egress. TA resides within the lumen of the endoplasmic reticulum (ER)/NE and functions in maintaining normal NE architecture. We show that perturbation of TA normal function by overexpressing torsinA wild type ( Following capsid assembly and DNA packaging, herpesvirus DNA-containing capsids in the nucleus translocate through the nuclear envelope (NE) into the cytoplasm by envelopment at the inner nuclear membrane (INM), followed rapidly by deenvelopment at the outer nuclear membrane (ONM). Between envelopment and de-envelopment, enveloped capsids called primary virions reside briefly in the perinuclear space that is contiguous with the lumen of the endoplasmic reticulum (ER) (reviewed in reference 34).Nuclear envelopment requires expression of the viral pUL31 and pUL34 (7,14,27,44,48). These proteins form a complex that is targeted to the NE and anchored in the membrane by the transmembrane domain of pUL34 (44,45,64,65). The pUL34/ pUL31 complex coordinates multiple events in nuclear egress, including disruption of the nuclear lamina, selection of DNAcontaining capsids for envelopment, budding of capsids into the INM, and de-envelopment and release of capsids at the ONM (2,30,38,43,46,53). pUL31 and pUL34 are incorporated into the perinuclear virion and are ordinarily lost from the egressing capsid upon de-envelopment at the ONM (14, 27, 31, 42, 45). Thus, they are not associated with cytoplasmic egress intermediates or with the mature virion that is released from the cell.De-envelopment may be inhibited and/or delayed by mutations in several herpes simplex virus (HSV) gene products. Mutations that eliminate either the expression or kinase activity of pUS3 result in accumulation of primary virions in the perinuclear space. During infection with these mutants, the perinuclear space expands by bulging into the nucleoplasm, perhaps because the exaggerated disruption of the nuclear lamina associated with loss of pUS3 function makes this the path of least resistance (2, 28, 36-38, 45, 49). A de-envelopment defect is also observed in cells infected with recombinant mutants of HSV-1 that fail to express both of the envelope glycoproteins gB and gH (13).Infection with HSV-1 alters the morphology and structure of the NE. The nucleus expands and changes shape. In addition, redistribution of nuclear lamina proteins is observed, most likely due to phosphorylation-mediated loss of protein-protein interactions (2,30,35,36,43,49,50,53,54). In addition to these changes, formation of perinuclear primary virions is likely to be accompanied by alteration of interactions that maintain spacing between the INM and ONM.The product of the DYT...
BackgroundPeptide receptor radionuclide therapy (PRRT) is an effective form of treatment for patients with metastatic neuroendocrine tumors (NETs). However, delivering sufficient radiation dose to the tumor to result in a high percentage of long-term tumor remissions remains challenging because of the limits imposed on administered activity levels by radiation damage to normal tissues. The goal of this study was to evaluate the dosimetric advantages of adding 131I meta-iodobenzylguanidine (131I-MIBG) to 90Y DOTA Phe1-Tyr3-octreotide (90Y-DOTATOC) in patients with advanced stage midgut NETs.MethodsTen patients were imaged simultaneously with 131I-MIBG and 111In-pentetreotide (as a surrogate for 90Y-DOTATOC) on days 1, 2, and 3 post-administration. Blood samples were obtained at the same time points. Using dosimetry measures from this data and our previously published methodology for calculating optimal combined administered activity levels for therapy, we determined the amount of 131I-MIBG that could be added to 90Y-DOTATOC without exceeding normal organ dose limits (marrow and kidneys) along with the expected increase in associated tumor dose, if any.ResultsWe found that a median value of 34.6 GBq of 131I-MIBG could be safely added to 90Y-DOTATOC (delivered over multiple cycles) by reducing the maximum total deliverable 90Y-DOTATOC by a median value of 24.5%. Taking this treatment approach, we found that there would be a median increase in deliverable tumor dose of 4,046 cGy in six of the ten subjects. Of note, there were a small number of metastases that were positive for only one or the other of these radiopharmaceuticals within the same subject.ConclusionsWe conclude that approximately half of the patients with midgut NETs that are eligible for PRRT could reasonably be expected to benefit from the addition of 131I-MIBG to 90Y-DOTATOC.
The impact of bariatric surgery (BS) on kidney transplantation (KT) outcomes in patients with obesity remains controversial. We systematically searched MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for studies reporting outcomes of KT recipients that underwent prior BS. Common/random effects metaanalyses were performed to obtain summary ratios of the postoperative outcomes. Eighteen eligible studies involving 315 patients were identified. Sleeve gastrectomy was the most common BS type (65.7%) followed by Roux-en-Y gastric bypass (27.6%) and gastric banding (4.4%). Across studies that provided the data, the %excess weight loss from BS to KT was 62.79% (95% confidence interval [CI], 52.01-73.56; range, 46.2%-80.3%). The rates of delayed graft function and acute rejection were 16% (95% CI, 7%-28%) and 16% (95% CI, 11%-23%) in 14 and 11 studies that provided this data, respectively. The rates of wound, urinary, and vascular complications following KT were 5% (95% CI, 0%-13%),19% (95% CI, 2%-42%), and 2% (95% CI, 0%-5%), in 12, 9, and 11 studies that provided this data, respectively. Follow-up time after KT was reported in 11 studies (61.1%) and ranged from 16 mo to >5 y. Graft loss was reported in 14 studies with an average of 3% (95% CI, 1%-6%). Four studies that included a comparator group of patients with obesity who did not undergo BS before KT showed comparable outcomes between the groups. We conclude that currently there is a paucity of robust evidence to suggest that pretransplant BS has a major effect on post-KT outcomes. High-quality studies are needed to fully evaluate the impact of BS on KT outcomes.
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