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Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac239-infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8+T cells in lymph nodes and reduced expression of BCL-2 in CD4+T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4+and CD8+T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART.

Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68lowmonocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68himonocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68lowand CD68himonocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.

The effectiveness of acupuncture for chronic low back pain (cLBP) has not been studied specifically in the 65-and-older population. To inform the validity and generalizability of future acupuncture studies among older adults, we characterized elderly participants’ prior experience with and views toward acupuncture and tested for clinical and sociodemographic differences between acupuncture-naïve and non-naïve participants.

COVID-19 may predispose patients to an increased risk of thrombotic complications through various pathophysiological mechanisms. Most of the reports on a high incidence of thrombotic complications are in relation to deep vein thrombosis and pulmonary embolism, while the evidence about arterial thrombosis in patients with COVID-19 is limited. We describe 4 cases of aortic thrombosis and associated ischemic complications in patients with severe SARS-CoV-2 infection.

ObjectiveHelicobacter pyloricauses life-long colonisation of the gastric mucosa, leading to chronic inflammation with increased risk of gastric cancer. Research on the pathogenesis of this infection would strongly benefit from an authentic human in vitro model.DesignAntrum-derived gastric glands from surgery specimens served to establish polarised epithelial monolayers via a transient air–liquid interface culture stage to study cross-talk with H. pyloriand the adjacent stroma.ResultsThe resulting ‘mucosoid cultures’, so named because they recapitulate key characteristics of the gastric mucosa, represent normal stem cell-driven cultures that can be passaged for months. These highly polarised columnar epithelial layers encompass the various gastric antral cell types and secrete mucus at the apical surface. By default, they differentiate towards a foveolar, MUC5AC-producing phenotype, whereas Wnt signalling stimulates proliferation of MUC6-producing cells and preserves stemness—reminiscent of the gland base. Stromal cells from the lamina propria secrete Wnt inhibitors, antagonising stem-cell niche signalling and inducing differentiation. On infection with H. pylori, a strong inflammatory response is induced preferentially in the undifferentiated basal cell phenotype. Infection of cultures for several weeks produces foci of viable bacteria and a persistent inflammatory condition, while the secreted mucus establishes a barrier that only few bacteria manage to overcome.ConclusionGastric mucosoid cultures faithfully reproduce the features of normal human gastric epithelium, enabling new approaches for investigating the interaction of H. pyloriwith the epithelial surface and the cross-talk with the basolateral stromal compartment. Our observations provide striking insights in the regulatory circuits of inflammation and defence.

The exterior of a hotel is equally important as the interior; what guests observe as they drive up or prospective guests see as they drive by is a direct reflection [...]

I appreciated the Editor's Letter ['Body Love,' Vol. 25#2], which mentioned skinny shaming. I have had similar body issues my whole life. I mostly shop at the 'Juniors' section in [...]

Prior studies support the utility of high sensitivity troponin I (hsTnI) for cardiovascular disease (CVD) risk stratification among asymptomatic populations; however, only two prior studies examined women separately. The association between hsTnI and breast arterial calcification is unknown.

ABSTRACTLive attenuated bacteria hold great promise as multivalent mucosal vaccines against a variety of pathogens. A major challenge of this approach has been the successful delivery of sufficient amounts of vaccine antigens to adequately prime the immune system without overattenuating the live vaccine. Here we used a live attenuated Salmonella entericaserovar Typhi strain to create a bivalent mucosal plague vaccine that produces both the protective F1 capsular antigen of Yersinia pestisand the LcrV protein required for secretion of virulence effector proteins. To reduce the metabolic burden associated with the coexpression of F1 and LcrV within the live vector, we balanced expression of both antigens by combining plasmid-based expression of F1 with chromosomal expression of LcrV from three independent loci. The immunogenicity and protective efficacy of this novel vaccine were assessed in mice by using a heterologous prime-boost immunization strategy and compared to those of a conventional strain in which F1 and LcrV were expressed from a single low-copy-number plasmid. The serum antibody responses to lipopolysaccharide (LPS) induced by the optimized bivalent vaccine were indistinguishable from those elicited by the parent strain, suggesting an adequate immunogenic capacity maintained through preservation of bacterial fitness; in contrast, LPS titers were 10-fold lower in mice immunized with the conventional vaccine strain. Importantly, mice receiving the optimized bivalent vaccine were fully protected against lethal pulmonary challenge. These results demonstrate the feasibility of distributing foreign antigen expression across both chromosomal and plasmid locations within a single vaccine organism for induction of protective immunity.

Reduced-intensity conditioning (RIC) regimens frequently provide insufficient disease control in patients with high-risk hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated intensification of fludarabine/busulfan (Flu/Bu) RIC with targeted marrow irradiation (TMI) in a dose escalation with expansion phase I clinical trial. TMI doses were delivered at 1.5 Gy in twice daily fractions on days -10 through -7 (dose levels: 3 Gy, 4.5 Gy, and 6 Gy), Flu (30 mg/m2for 5 days) and Bu (area under the curve, 4800 µM*minute for 2 days). Eligible patients were age ≥18 years with high-risk hematologic malignancy and compromised organ function ineligible for myeloablative transplantation (n = 26). The median patient age was 64 years (range, 25 to 76 years). Nineteen patients (73%) had active or measurable residual disease at transplantation. One-year disease-free survival and overall survival were 55% (95% confidence interval [CI], 34% to 76%) and 65% (95% CI, 46% to 85%), respectively. Day +100 and 1 year transplantation-related mortality were 4% (95% CI, 0.6% to 27%) and 8.5% (95% CI, 2% to 32%), respectively. The 1-year cumulative incidence of relapse was 43% (95% CI, 27% to 69%). Rates of grade II-IV and III-IV acute GVHD rates were 57% (95% CI, 39% to 84%) and 22% (95% CI, 9% to 53%), respectively. Whole blood immune profiling demonstrated enrichment of central/transitional memory-like T cells with higher TMI doses, which correlated with improved survival compared with control samples from patients undergoing allogeneic HSCT. Intensification of a Flu/Bu RIC regimen with TMI is feasible with a low incidence of transplantation-related mortality in medically frail patients with advanced malignancies. The recommended phase 2 TMI dose is 6 Gy.

While a number of solid tumors are identified as obesity-associated cancers, multiple myeloma and acute promyelocytic leukemia (APL) are the only hematologic malignancies included in this category. APL is a highly treatable form of AML characterized by maturation arrest at the promyelocyte stage, and frequent cures with combined ATRA and Arsenic Trioxide therapy. APL is initiated by a chromosomal translocation that causes the fusion of thePMLandRARAgenes, leading to the production of PML-RARA protein. To determine if obesity accelerates the development of APL, we used a genetically-engineered knock-in model in which human PML-RARA cDNA was inserted into the 5’ untranslated region of the murine cathepsin G gene (Ctsg), which targets expression to early myeloid progenitor cells. This knock-in transgene was extensively backcrossed (>20 generations) into the C57BL/6J (B6) genetic background, which has been consistently shown to render mice susceptible to diet-induced obesity.Ctsg-PML-RARA mice developed on the B6 background generate a lethal APL-like leukemia with a latency of 8-12 months, and a penetrance of about 60%, as cooperating mutations occur and cause clinical disease.

Shigella spp. are food- and waterborne pathogens that cause severe diarrheal and dysenteric disease associated with high morbidity and mortality. Individuals most often affected are children under 5 years of age in the developing world. The existence of multiple Shigella serotypes and the heterogenic distribution of pathogenic strains, as well as emerging antibiotic resistance, require the development of a broadly protective vaccine. All Shigella spp. utilize a type III secretion system (TTSS) to initiate infection. The type III secretion apparatus (TTSA) is the molecular needle and syringe that form the energized conduit between the bacterial cytoplasm and the host cell to transport effector proteins that manipulate cellular processes to benefit the pathogen. IpaB and IpaD form a tip complex atop the TTSA needle and are required for pathogenesis. Because they are common to all virulent Shigella spp., they are ideal candidate antigens for a subunit-based, broad-spectrum vaccine. We examined the immunogenicity and protective efficacy of IpaB and IpaD, alone or combined, coadministered with a double mutant heat-labile toxin (dmLT) from Escherichia coli, used as a mucosal adjuvant, in a mouse model of intranasal immunization and pulmonary challenge. Robust systemic and mucosal antibody- and T cell-mediated immunities were induced against both proteins, particularly IpaB. Mice immunized in the presence of dmLT with IpaB alone or IpaB combined with IpaD were fully protected against lethal pulmonary infection with Shigella flexneri and Shigella sonnei. We provide the first demonstration that the Shigella TTSAs IpaB and IpaD are promising antigens for the development of a cross-protective Shigella vaccine.

Shigellaspp. are food- and waterborne pathogens that cause severe diarrheal and dysenteric disease associated with high morbidity and mortality. Individuals most often affected are children under 5 years of age in the developing world. The existence of multiple Shigellaserotypes and the heterogenic distribution of pathogenic strains, as well as emerging antibiotic resistance, require the development of a broadly protective vaccine. All Shigellaspp. utilize a type III secretion system (TTSS) to initiate infection. The type III secretion apparatus (TTSA) is the molecular needle and syringe that form the energized conduit between the bacterial cytoplasm and the host cell to transport effector proteins that manipulate cellular processes to benefit the pathogen. IpaB and IpaD form a tip complex atop the TTSA needle and are required for pathogenesis. Because they are common to all virulent Shigellaspp., they are ideal candidate antigens for a subunit-based, broad-spectrum vaccine. We examined the immunogenicity and protective efficacy of IpaB and IpaD, alone or combined, coadministered with a double mutant heat-labile toxin (dmLT) from Escherichia coli, used as a mucosal adjuvant, in a mouse model of intranasal immunization and pulmonary challenge. Robust systemic and mucosal antibody- and T cell-mediated immunities were induced against both proteins, particularly IpaB. Mice immunized in the presence of dmLT with IpaB alone or IpaB combined with IpaD were fully protected against lethal pulmonary infection with Shigella flexneriand Shigella sonnei. We provide the first demonstration that the ShigellaTTSAs IpaB and IpaD are promising antigens for the development of a cross-protective Shigellavaccine.

Background:AntiCD19 CAR-T cells are effective against chemorefractory B cell lymphoma. Patients (pts) with rapidly progressive disease and urgent need for therapy have very poor prognosis and may not be able to receive CAR-T cells in time. Decreasing the apheresis to infusion time can make CAR-T cells rapidly available. We conducted a dual-center phase I trial using on-site manufacture of CAR-T cells for treatment of relapsed and refractory (r/r) B cell lymphoma.

Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth of tumors but often leads to the emergence of slowly dividing persister cells, which constitute a reservoir for the selection of drug-resistant clones. In BRAFV600Emelanomas, RAF and MEK inhibitors efficiently block oncogenic signaling, but persister cells emerge. Here, we show that persister cells escape drug-induced cell-cycle arrest via brief, sporadic ERK pulses generated by transmembrane receptors and growth factors operating in an autocrine/paracrine manner. Quantitative proteomics and computational modeling show that ERK pulsing is enabled by rewiring of mitogen-activated protein kinase (MAPK) signaling: from an oncogenic BRAFV600Emonomer-driven configuration that is drug sensitive to a receptor-driven configuration that involves Ras-GTP and RAF dimers and is highly resistant to RAF and MEK inhibitors. Altogether, this work shows that pulsatile MAPK activation by factors in the microenvironment generates a persistent population of melanoma cells that rewires MAPK signaling to sustain non-genetic drug resistance.

Mammographic Breast arterial calcification (BAC) may be a novel subclinical cardiovascular disease (CVD) risk marker. Since subclinical and clinical CVD are associated with cognitive impairment, we set out to investigate whether there is a relation between BAC presence/severity and cognitive function (CF). We used data from the MultIethNic study of brEast aRterial calcium gradation and cardioVAscular disease (MINERVA), a multiethnic cohort of women aged 60-79 at baseline (10/2012 and 2/2015) who were free of symptomatic CVD, all recruited at Kaiser Permanente of Northern California. The sample available for analyses with complete data on BAC, cognitive function and covariates was 3,919 (mean ± SD age=67 ± 4, 52% white, 18% Asian, 15% African-American and 12% Latina). A BAC continuous mass score (mg) was obtained using a validated densitometry method. BAC presence was BAC score > 0 mg, and severe BAC was BAC score > 20 mg. CF was dichotomized as Montreal Cognitive Assessment (MoCA) score < 23 (first quartile) vs ≥ 23 (quartiles 2, 3 and 4). The unadjusted (Model 1) odds ratios (OR, 95% CI; p-value) of CF < 23 vs. ≥ 23 associated with BAC > 0 vs. BAC=0 was 1.15 (0.98-1.35; 0.08). However, adjustment for age, race and education (Model 2) abolished this association. Further adjustment for factors independently predicting CF (Model 3, with further inclusion of diabetes, HDL-C, CES depression score, breast feeding, multiple sclerosis and osteoarthitis) did not change the association. The unadjusted (Model 1) odds ratios (OR, 95% CI; p-value) of CF < 23 vs. ≥ 23 associated with BAC > 20 vs. BAC≤ 20 was 1.44 (1.02-2.01; 0.04). However, adjustment for age, race and education (Model 2) abolished this association and further adjustment for factors independently predicting CF did not alter the association. In conclusion, we found a statistically significant association between severe BAC and CF, but it was explained by covariation (confounding) by age, race and education, arguing that BAC may not play a role in cognitive impairment.

Several letters to the editor are presented including one in response to the article "Breaking the Silence" in Vol 25 No. 2 issue, another in response to the Editor's Letter "Body Love" in Vol 25 No. 2 and another in response to the "Happily Ever After" snapshots.

No relevant conflicts of interest to declare.