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Tailoring stress responses When faced with environmental stress, cells respond by shutting down cellular processes such as translation and nucleocytoplasmic transport. At the same time, cells preserve cytoplasmic messenger RNAs in structures known as stress granules, and many cellular proteins are modified by the covalent addition of ubiquitin, which has long been presumed to reflect degradation of stress-damaged proteins (see the Perspective by Dormann). Maxwell et al. show that cells generate distinct patterns of ubiquitination in response to different stressors. Rather than reflecting the degradation of stress-damaged proteins, this ubiquitination primes cells to dismantle stress granules and reinitiate normal cellular activities once the stress is removed. Gwon et al. show that persistent stress granules are degraded by autophagy, whereas short-lived granules undergo a process of disassembly that is autophagy independent. The mechanism of this disassembly depends on the initiating stress. Science , abc3593 and abf6548, this issue p. eabc3593 and p. eabf6548 ; see also abj2400, p. 1393

OBJECTIVES: To evaluate the efficacy of the simultaneous hypertonic saline solution and IV furosemide (HSS+Fx) for patients with fluid overload compared with IV furosemide alone (Fx). DATA SOURCES: Electronic databases (MEDLINE, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, PsycINFO, Scopus, and WOS) were searched from inception to March 2020. STUDY SELECTION: Randomized controlled trials on the use of HSS+Fx in adult patients with fluid overload versus Fx were included. DATA EXTRACTION: Data were collected on all-cause mortality, hospital length of stay, heart failure–related readmission, along with inpatient weight loss, change of daily diuresis, serum creatinine, and 24-hour urine sodium excretion from prior to post intervention. Pooled analysis with random effects models yielded relative risk or mean difference with 95% CIs. DATA SYNTHESIS: Eleven randomized controlled trials comprising 2,987 acute decompensated heart failure patients were included. Meta-analysis demonstrated that HSS+Fx was associated with lower all-cause mortality (relative risk, 0.55; 95% CI, 0.46–0.67; p < 0.05; I2 = 12%) and heart failure–related readmissions (relative risk, 0.50; 95% CI, 0.33–0.76; p < 0.05; I2 = 61%), shorter hospital length of stay (mean difference, –3.28 d; 95% CI, –4.14 to –2.43; p < 0.05; I2 = 93%), increased daily diuresis (mean difference, 583.87 mL; 95% CI, 504.92–662.81; p < 0.05; I2 = 76%), weight loss (mean difference, –1.76 kg; 95% CI, –2.52 to –1.00; p < 0.05; I2 = 57%), serum sodium change (mean difference, 6.89 mEq/L; 95% CI, 4.98–8.79; p < 0.05; I2 = 95%), and higher 24-hour urine sodium excretion (mean difference, 61.10 mEq; 95% CI, 51.47–70.73; p < 0.05; I2 = 95%), along with decreased serum creatinine (mean difference, –0.46 mg/dL; 95% CI, –0.51 to –0.41; p < 0.05; I2 = 89%) when compared with Fx. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from low to moderate. CONCLUSIONS: Benefits of the HSS+Fx over Fx were observed across all examined outcomes in acute decompensated heart failure patients with fluid overload. There is at least moderate certainty that HSS+Fx is associated with a reduction in mortality in patients with acute decompensated heart failure. Factors associated with a successful HSS+Fx utilization are still unknown. Current evidence cannot be extrapolated to other than fluid overload states in acute decompensated heart failure.

Since its emergence at the end of 2019, SARS-CoV-2, the causative agent of COVID-19, has caused over 100 million infections and 2.4 million deaths worldwide. Recently, countries have begun administering approved COVID-19 vaccines, which elicit strong immune responses and prevent disease in most vaccinated individuals.

PurposeTo address the need for a method to acquire 3D data for MR elastography (MRE) of the whole brain with substantially improved spatial resolution, high SNR, and reduced acquisition time compared with conventional methods.MethodsWe combined a novel 3D spiral staircase data‐acquisition method with a spoiled gradient‐echo pulse sequence and MRE motion‐encoding gradients (MEGs). The spiral‐out acquisition permitted use of longer‐duration motion‐encoding gradients (ie, over two full oscillatory cycles) to enhance displacement SNR, while still maintaining a reasonably short TE for good phase‐SNR. Through‐plane parallel imaging with low noise penalties was implemented to accelerate acquisition along the slice direction. Shared anatomical information was exploited in the deblurring procedure to further boost SNR for stiffness inversion.ResultsIn vivo and phantom experiments demonstrated the feasibility of the proposed method in producing brain MRE results comparable to the spin‐echo–based approaches, both qualitatively and quantitatively. High‐resolution (2‐mm isotropic) brain MRE data were acquired in 5 minutes using our method with good SNR. Joint deblurring with shared anatomical information produced SNR‐enhanced images, leading to upward stiffness estimation.ConclusionA novel 3D gradient‐echo–based approach has been designed and implemented, and shown to have promising potential for fast and high‐resolution in vivo MRE of the whole brain.

Getting around the blood–brain barrier The meninges comprise three membranes that surround and protect the central nervous system (CNS). Recent studies have noted the existence of myeloid cells resident there, but little is known about their ontogeny and function, and whether other meningeal immune cell populations have important roles remains unclear (see the Perspective by Nguyen and Kubes). Cugurra et al. found in mice that a large proportion of continuously replenished myeloid cells in the dura mater are not blood derived, but rather transit from cranial bone marrow through specialized channels. In models of CNS injury and neuroinflammation, the authors demonstrated that these myeloid cells have an immunoregulatory phenotype compared with their more inflammatory blood-derived counterparts. Similarly, Brioschi et al. show that the meninges host B cells that are also derived from skull bone marrow, mature locally, and likely acquire a tolerogenic phenotype. They further found that the brains of aging mice are infiltrated by a second population of age-associated B cells, which come from the periphery and may differentiate into autoantibody-secreting plasma cells after encountering CNS antigens. Together, these two studies may inform future treatment of neurological diseases. Science , abf7844, abf9277, this issue p. eabf7844 , p. eabf9277 ; see also abj8183, p. 396

2500 Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach for relapsed refractory hematologic malignancies. The Indiana strain of Vesicular Stomatitis Virus was engineered to encode interferon beta (IFNβ) and sodium iodine symporter (NIS) to produce VSV-IFNβ-NIS. Virally encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. NIS was inserted to noninvasively assess viral biodistribution using SPECT/PET imaging. We present the results of the phase 1 clinical trial NCT03017820 of systemic administration of VSV-IFNβ-NIS among patients (pts) with relapsed refractory Multiple Myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leukemia (AML). Methods: VSV-IFNβ-NIS was administered at 5x109 TCID50 (50% tissue culture infectious dose) dose level 1 to dose level 4, 1.7x1011 TCID50. The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNβ-NIS. Correlative objectives included monitoring viremia and virus shedding. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: 15 pts received VSV-IFNβ-NIS: MM (7), TCL(7) and AML(1); 3 pts were treated at each dose level (DL) 1 through 3 (respectively 0.05, 0.17, and 0.5 x 1011 TCID50), & 6 pts were treated at dose level 4 (1.7x1011 TCID50). There were no dose limiting toxicities. The most frequent grades 3 & 4 AEs were hematologic: lymphopenia (46.6 & 26.6%), neutropenia (13.3% & 6.7%). CRS grades 1 (6.7%) and 2 (46.6%) were the non-hematologic AEs of note; mostly at DL 4. Only 1 pt required transient pressor support. Responses were seen in pts with T cell lymphoma. At DL2, there was a partial response (PR) lasting 3 months in a pt, post 12 prior lines of therapy. At DL4 there was a 6 month PR in a pt with PTCL and another pt with cutaneous relapse of PTCL who enjoys an ongoing CR, more than 1 year post VSV infusion; both pts received 5 prior lines of therapy. Viremia was detected in all pts at the end of infusion only up to 72 hrs post infusion; no infectious virus was recovered in buccal swabs or urine. Neutralizing anti-VSV antibodies were present by day 29. IFN levels were detectable within 30 mins of infusion, peaking between 4 & 48 hrs. TCL pts mounted higher hIFNβ levels within 48 hrs; the pt with CR mounted peak hIFNβ response of 18213.3pg/ml at 48 hrs post infusion, 15-fold higher than any other pt. Conclusions: VSV-IFNβ-NIS can be safely administered by IV infusion among heavily pretreated pts with hematologic malignancies. VSV-IFNβ-NIS as a single agent appears to be most effective at DL4 among patients with TCL, with an ongoing CR in a patient at DL4 more than 1 year post administration. Future trials of combination strategies with immune-modulatory drugs are currently being planned. Clinical trial information: NCT03017820.

AbstractHigh‐grade gliomas (HGGs) are aggressive, treatment‐resistant, and often fatal human brain cancers. The TNF‐like weak inducer of apoptosis (TWEAK)/fibroblast growth factor‐inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild‐type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication‐competent avian sarcoma‐leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural‐like gliomas led to the development of highly invasive and lethal brain cancer with striking biological features including extensive pseudopalisading necrosis, constitutive canonical and noncanonical NF‐κB pathway signaling, and high plasminogen activator inhibitor‐1 (PAI‐1) expression. Analyses of HGG patient datasets revealed that high human PAI‐1 gene (SERPINE1) expression correlates with shorter patient survival, and that the SERPINE1 and Fn14 (TNFRSF12A) genes are frequently co‐expressed in bulk tumor tissues, in tumor subregions, and in malignant cells residing in the tumor microenvironment. These findings provide new insights into the potential importance of Fn14 in human HGG pathobiology and designate both the NF‐κB signaling node and PAI‐1 as potential targets for therapeutic intervention.Main PointsThis work demonstrates that elevated levels of the TWEAK receptor Fn14 in tumor‐initiating, neural progenitor cells leads to the transformation of proneural‐like gliomas into more aggressive and lethal tumors that exhibit constitutive NF‐κB pathway activation and plasminogen activator inhibitor‐1 overexpression.

ABSTRACT Introduction: The impact of albumin resuscitation on sepsis outcomes is debated, particularly in the initial phase of resuscitation. We aimed to investigate the association between albumin use in the initial 6 h of resuscitation and subsequent outcomes in adult septic patients. Methods: This single-center, retrospective, propensity score-matched cohort study included adult patients admitted to intensive care units (ICUs) with sepsis or septic shock from January 1, 2006, to May 4, 2018, at a tertiary referral hospital. We compared two groups based on albumin receipt within the initial six resuscitation hours (albumin group vs. non-albumin group). We performed a 1:2 propensity score matching to assess shock-free time in ICU as the primary outcome. Results: Of 2,732 patients with medical sepsis, 286 cases in the albumin group were matched with 549 individuals in the non-albumin group. Compared to the non-albumin group, the albumin group required more intravenous fluids and had higher net fluid balance, lower mean arterial pressure, and lower serum base excess level in the initial 6 and 24 h of resuscitation. Shock-free time, ICU and hospital length of stay, and 28-day mortality were not different between albumin and non-albumin groups (56 vs. 66 h, P = 0.18; 3.5 days vs. 3.7 days, P = 0.61; 9.1 days vs. 9.5 days, P = 0.27; 36% vs. 32%, P = 0.25, respectively). Conclusions: Using albumin during the initial 6 h of resuscitation was not associated with benefits in clinical outcomes of patients with medical sepsis.

Background: Left ventricular outflow tract (LVOT) obstruction is an important determinant in management of hypertrophic cardiomyopathy (HCM). Valsalva maneuver and amyl nitrite are used in clinical practice during resting echocardiography to induce latent obstruction (LVOT gradient <30 mmHg at rest, ≥30 mmHg with maneuver). With a nationwide shortage of amyl nitrite in 2019, we implemented a “repetitive squat-to-stand” maneuver to provoke LVOT obstruction during echocardiography. Methods: Patients with known or suspected HCM without resting obstruction who underwent repetitive squat-to-stand maneuver during echocardiography between February and September 2019 were included. Maximal instantaneous gradients were recorded. Provocable gradients were compared utilizing a two-sided t-test. Amyl nitrite was not available during the study period. Results: Squat-to-stand assessments were available in 125 patients without resting obstruction (age 58 ± 15 years, 67% male); 114 also performed Valsalva maneuver. 47 of 125 patients (37.6%) demonstrated provocable obstruction. 46 (36.8%) demonstrated latent obstruction provoked by squat-to-stand, which was severe (gradient ≥50 mmHg) in 29 (23.2%). Of the 46 patients, 19 demonstrated latent obstruction only with squat-to-stand but not with Valsalva, 13 of which demonstrated severe obstruction. Among patients with latent obstruction who performed both Valsalva and squat-to-stand maneuver (n=41), squat-to-stand resulted in a higher gradient than Valsalva maneuver (p<0.0001, Figure). Conclusion: Repetitive squat-to-stand maneuver is a clinically useful adjunct to the traditional echocardiographic exam in HCM. This maneuver appears to be more sensitive than the Valsalva maneuver for identifying severe dynamic LVOT obstruction. Use of repetitive squat-to-stand warrants further study in comparison to amyl nitrite, particularly regarding cost savings and diagnostic performance.