New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically ...modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft-versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD. This trial was registered at www.clinicaltrials.gov as #NCT01087294.
•Donor-derived anti-CD19-CAR T cells cause regressions of refractory malignancies after allogeneic transplantation.
Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had ...brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients’ fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.
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•Bi-allelic DBR1 mutations are found in patients with viral infection of the brainstem•The DBR1 mutant alleles are severely hypomorphic in terms of expression and function•The levels of RNA lariats are increased in DBR1-mutated patients’ fibroblasts•Cell-intrinsic immunity to viruses is impaired in DBR1-mutated patients’ fibroblasts
Autosomal recessive DBR1 deficiency underlies a cellular accumulation of RNA lariats, resulting in patient susceptibility to severe viral infections of the brainstem.
Here, Rosenberg examines the difficulties tsarist military censors had in accessing the moods of Russian soldiers during World War I through their correspondence, a task deemed essential to prevent ...dissidence and deploy army units effectively. His article is based on a rich trove of archival materials revealing the ways in which censors configured soldiers' emotions within circulating fields of assumption and expectation, filtering their expression into "useful" categories at some distance from their actual emotional fields. While these documents may have served the needs of military commanders, they also reflected processes of mediation that were not ultimately in the army's interests. In analyzing these processes, he uses historical specificities to raise a more general question on the ways in which emotions are read make it more difficult for historians to access them. In other words, when expressions of emotions in their sources are filtered through their own social and cultural norms, it is hard to see for sure that the feelings being described reflect what was actually felt.
Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of ...LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes.
We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes.
Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified.
This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.
This essay looks at the ways our understanding of the Russian revolution was conditioned by contemporary narratives of progress and change, and how these narratives and the "historical imaginations" ...that created them also influenced later tellings of the "great story." In this way it attempts to reposition the grave problems Russia faced especially after 1914 in terms of the actual and proposed solutions offered by historical actors, and evaluates their effectiveness as well as their relation especially to the evolving meanings of revolution. In the process, it emphasizes the subjective aspects of problems like scarcity and personal loss, and how these might not have been amenable to the rational logics of state administration.
C1q/TNF-related protein 1 (CTRP1) is an endocrine factor with metabolic, cardiovascular, and renal functions. We previously showed that aged
knockout (KO) mice fed a control low-fat diet develop ...renal hypertrophy and dysfunction. Since aging and obesity adversely affect various organ systems, we hypothesized that aging, in combination with obesity induced by chronic high-fat feeding, would further exacerbate renal dysfunction in CTRP1-deficient animals. To test this, we fed wild-type and
KO mice a high-fat diet for 8 mo or longer. Contrary to our expectation, no differences were observed in blood pressure, heart function, or vascular stiffness between genotypes. Loss of CTRP1, however, resulted in an approximately twofold renal enlargement (relative to body weight), ∼60% increase in urinary total protein content, and elevated pH, and changes in renal gene expression affecting metabolism, signaling, transcription, cell adhesion, solute and metabolite transport, and inflammation. Assessment of glomerular integrity, the extent of podocyte foot process effacement, as well as renal response to water restriction and salt loading did not reveal significant differences between genotypes. Interestingly, blood platelet, white blood cell, neutrophil, lymphocyte, and eosinophil counts were significantly elevated, whereas mean corpuscular volume and hemoglobin were reduced in
-KO mice. Cytokine profiling revealed increased circulating levels of CCL17 and TIMP-1 in KO mice. Compared with our previous study, current data suggest that chronic high-fat feeding affects renal phenotypes differently than similarly aged mice fed a control low-fat diet, highlighting a diet-dependent contribution of CTRP1 deficiency to age-related changes in renal structure and function.
Objective To delineate the phenotypic and molecular spectrum of patients with a syndromic variant of severe congenital neutropenia (SCN) due to mutations in the gene encoding glucose-6-phosphatase ...catalytic subunit 3 (G6PC3). Study design Patients with syndromic SCN were characterized for associated malformations and referred to us for G6PC3 mutational analysis. Results In a cohort of 31 patients with syndromic SCN, we identified 16 patients with G6PC3 deficiency including 11 patients with novel biallelic mutations. We show that nonhematologic features of G6PC3 deficiency are good predictive indicators for mutations in G6PC3. Additionally, we demonstrate genetic variability in this disease and define novel features such as growth hormone deficiency, genital malformations, disrupted bone remodeling, and abnormalities of the integument. G6PC3 mutations may be associated with hydronephrosis or facial dysmorphism. The risk of transition to myelodysplastic syndrome/acute myeloid leukemia may be lower than in other genetically defined SCN subgroups. Conclusions The phenotypic and molecular spectrum in G6PC3 deficiency is wider than previously appreciated. The risk of transition to myelodysplastic syndrome or acute myeloid leukemia may be lower in G6PC3 deficiency compared with other subgroups of SCN.
Local and systemic factors that influence renal structure and function in aging are not well understood. The secretory protein C1q/TNF‐related protein 1 (CTRP1) regulates systemic metabolism and ...cardiovascular function. We provide evidence here that CTRP1 also modulates renal physiology in an age‐ and sex‐dependent manner. In mice lacking CTRP1, we observed significantly increased kidney weight and glomerular hypertrophy in aged male but not female or young mice. Although glomerular filtration rate, plasma renin and aldosterone levels, and renal response to water restriction did not differ between genotypes, CTRP1‐deficient male mice had elevated blood pressure. Echocardiogram and pulse wave velocity measurements indicated normal heart function and vascular stiffness in CTRP1‐deficient animals, and increased blood pressure was not due to greater salt retention. Paradoxically, CTRP1‐deficient mice had elevated urinary sodium and potassium excretion, partially resulting from reduced expression of genes involved in renal sodium and potassium reabsorption. Despite renal hypertrophy, markers of inflammation, fibrosis, and oxidative stress were reduced in CTRP1‐deficient mice. RNA sequencing revealed alterations and enrichments of genes in metabolic processes in CTRP1‐deficient animals. These results highlight novel contributions of CTRP1 to aging‐associated changes in renal physiology.
More than seventy years since the Bolsheviks came to power, there is still no comprehensive study of workers' activism in history's first successful workers' revolution. Strikes and Revolution in ...Russia, 1917 is the first effort in any language to explore this issue in both quantitative and qualitative terms and to relate strikes to the broader processes of Russia's revolutionary transformation. Diane Koenker and William Rosenberg not only provide a new basis for understanding essential elements of Russia's social and political history in this critical period but also make a strong contribution to the literature on European labor movements. Using statistical techniques, but without letting methodology dominate their discussion, the authors examine such major problems as the mobilization of labor and management, factory relations, perceptions, the formation of social identities, and the relationship between labor protest and politics in 1917. They challenge common assumptions by showing that much strike activity in 1917 can be understood as routine, but they are also able to demonstrate how the character of strikes began to change and why.
Originally published in 1990.
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