Mathematical model for IL-2-based cancer immunotherapy.

A basic mathematical model for IL-2-based cancer immunotherapy is proposed and studied. Our analysis shows that the outcome of therapy is mainly determined by three parameters, the relative death rate of CD4+ T cells, the relative death rate of CD8+ T cells, and the dose of IL-2 treatment. Minimal equilibrium tumor size can be reached with a large dose of IL-2 in the case that CD4+ T cells die out. However, in cases where CD4+ and CD8+ T cells persist, the final tumor size is independent of the IL-2 dose and is given by the relative death rate of CD4+ T cells. Two groups of in silico clinical trials show some short-term behaviors of IL-2 treatment. IL-2 administration can slow the proliferation of CD4+ T cells, while high doses for a short period of time over several days transiently increase the population of CD8+ T cells during treatment before it recedes to its equilibrium. IL-2 administration for a short period of time over many days suppresses the tumor population for a longer time before approaching its steady-state levels. This implies that intermittent administration of IL-2 may be a good strategy for controlling tumor size.

Xanthomonas Infection Transforms the Apoplast into an Accessible and Habitable Niche for Salmonella enterica.

The physiology of plant hosts can be dramatically altered by phytopathogens. Xanthomonas hortorum pv. gardneri is one such pathogen that creates an aqueous niche within the leaf apoplast by manipulating the plant via the transcription activator-like effector AvrHah1. Simultaneous immigration of X. hortorum pv. gardneri and Salmonella enterica to healthy tomato leaves results in increased survival of S. enterica as Xanthomonas infection progresses. However, the fate of S. enterica following arrival on actively infected leaves has not been examined. We hypothesized that the water soaking caused by X. hortorum pv. gardneri could facilitate the ingression of S. enterica into the apoplast and that this environment would be conducive for growth. We found that an altered apoplast, abiotically water congested or Xanthomonas infected and water-soaked, enabled surface S. enterica to passively localize to the protective apoplast and facilitated migration of S. enterica to distal sites within the aqueous apoplast. avrHah1 contributed to the protection and migration of S. enterica early in X. hortorum pv. gardneri infection. Xanthomonas-infected apoplasts facilitated prolonged survival and promoted S. enterica replication compared to the case with healthy apoplasts. Access to an aqueous apoplast in general protects S. enterica from immediate exposure to irradiation, whereas the altered environment created by Xanthomonas infection provides growth-conducive conditions for S. enterica. Overall, we have characterized an ecological relationship in which host infection converts an unreachable niche to a habitable environment. IMPORTANCE Bacterial spot disease caused by Xanthomonas species devastates tomato production worldwide. Salmonellosis outbreaks from consumption of raw produce have been linked to the arrival of Salmonella enterica on crop plants in the field via contaminated irrigation water. Considering that Xanthomonas is difficult to eradicate, it is highly likely that S. enterica arrives on leaves precolonized by Xanthomonas with infection under way. Our study demonstrated that infection and disease fundamentally alter the leaf, resulting in redistribution and change in abundance of a phyllosphere bacterial member. These findings contribute to our understanding of how S. enterica manages to persist on leaf tissue despite lacking the ability to liberate nutrients from plant cells. More broadly, this study reveals a mechanism by which physiochemical changes to a host environment imposed by a plant pathogen can convert an uninhabitable leaf environment into a hospitable niche for selected epiphytic microbes.

Success Rate of Wire Control-Assisted ERCP Sphincterotomy Versus Non-assisted ERCP Cannulation of Common Bile Duct in a Secondary Care Unit During the First COVID-19 Peak: A Retrospective Observational Study of 281 Patients.

Background The British Society of Gastroenterology (BSG) recommended that during the COVID-19 pandemic, endoscopy units perform endoscopic retrograde cholangiopancreatography (ERCP) for obstructive biliary pathologies in an emergency. We assessed the local performance of ERCP during the first wave of COVID-19 at our local endoscopy center, in particular the technique to common bile duct (CBD) cannulation. Methodology All ERCP procedures performed from January to June 2020 were retrospectively assessed and compared with procedures performed between January and June 2019 at the Royal Lancaster Infirmary. The indications for ERCP, success rate, and complications were studied separately. Correlation analysis was conducted using Spearman's rank correlation coefficient. The binary logistic regression model was used to compute the factors associated with successful ERCP. Significance was established when the two-sided P-value < 0.05. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software version 25 for Windows (SPSS Inc., Chicago, IL, USA, 2017). Results A total of 281 ERCP were included in this study, with 169 and 112 performed during the first six months of 2019 and 2020, respectively. A statistically significant (0.0087) higher proportion of cases with liver dysfunction presented for ERCP before the COVID-19 outbreak (152, 89.94%). All patients before COVID-19 underwent wire control-assisted ERCP, while 82 (73.21%) received assisted ERCP during the first wave (P < 0.001). There was no statistically significant difference (P = 0.10) in the number of patients who underwent sphincterotomy before and during the first wave of COVID-19, with 97 (57.39%) and 76 (67.85%), respectively. The success rate of ERCP before COVID-19 was relatively high, accounting for 146 (86.39%) patients in contrast to 87 (77.67%) patients during the first wave (P = 0.074). Sphincterotomy (ß = 2.800, P = 0.028) and stent insertion (ß = 0.852, P = 0.046) were statistically significant predictors of ERCP outcomes. There was no statistically significant impact of cholangitis on the success of ERCP (ß = 1.672, P = 0.109). Conclusion The first wave of COVID-19 had a statistically proven negative impact on the expected standards of ERCP performance. Although the complication rate was significantly higher during the first wave case difficulty, the American Society of Anesthesia (ASA) status was not assessed on an individual basis. Both ASA status and case difficulty are now included in our endoscopy selection process. We recommend adding the complexity of cases and ASA to the local and national recording databases. This is a rare study on UK-based hospitals.

Binding to any ESCRT can mediate ubiquitin-independent cargo sorting.

The ESCRT (endosomal sorting complex required for transport) machinery is known to sort ubiquitinated transmembrane proteins into vesicles that bud into the lumen of multivesicular bodies (MVBs). Although the ESCRTs themselves are ubiquitinated they are excluded from the intraluminal vesicles and recycle back to the cytoplasm for further rounds of sorting. To obtain insights into the rules that distinguish ESCRT machinery from cargo we analyzed the trafficking of artificial ESCRT-like protein fusions. These studies showed that lowering ESCRT-binding affinity converts a protein from behaving like ESCRT machinery into cargo of the MVB pathway, highlighting the close relationship between machinery and the cargoes they sort. Furthermore, our findings give insights into the targeting of soluble proteins into the MVB pathway and show that binding to any of the ESCRTs can mediate ubiquitin-independent MVB sorting.

Tolvaptan and its potential in the treatment of hyponatremia.

Tolvaptan is a selective arginine vasopressin (AVP) V(2) receptor blocker used to induce free water diuresis in the treatment of euvolemic or hypervolemic hyponatremia. Currently the orally active medication is in the final stages prior to approval by the FDA for outpatient therapy. It appears to be safe and effective at promoting aquaresis and raising serum sodium levels in both short- and long-term studies. Tolvaptan is also effective for treatment of congestive heart failure (CHF) exacerbation, but whether there are long standing beneficial effects on CHF is still controversial. Prolonged use of tolvaptan leads to increased endogenous levels of AVP and perhaps over-stimulation of V(1A) receptors. Theoretically this activation could lead to increased afterload and cardiac myocyte fibrosis, causing progression of CHF. However, after 52 weeks of tolvaptan therapy there was no worsening of left ventricular dilatation. In addition, tolvaptan is metabolized by the CYP3A4 system; thus physicians should be aware of the potential for increased interactions with other medications. Tolvaptan is a breakthrough in the therapy of hyponatremia as it directly combats elevated AVP levels associated with the syndrome of inappropriate secretion of antidiuretic hormone, congestive heart failure, and cirrhosis of the liver.