Despite improvements in prevention and treatment of acute graft‐versus‐host disease (GVHD), chronic GVHD (cGVHD) remains a significant contributor to morbidity and mortality of allogeneic transplant ...patients. Chronic GVHD remains a leading cause of late complications posttransplant and is impacted by donor‐, patient‐, and transplant‐related (hematopoietic cell transplant HCT) factors. Advances in the biological understanding of cGVHD have provided opportunities to improve clinical interventions for prevention and treatment. Expansion of posttransplantation cyclophosphamide beyond haploidentical HCTs has transformed alternative donor, matched, and mismatch GVHD outcomes and is currently being investigated in two upcoming clinical trials network prophylaxis studies. Although corticosteroids remain the cornerstone therapy, several clinical trials are prospectively investigating the utility of using novel agents in combination with corticosteroids as upfront therapy to mitigate prolonged steroid exposure. Several treatment options for patients with steroid‐refractory cGVHD are currently being investigated, and advances have resulted in ibrutinib becoming the first cGVHD agent approved by the U.S. Food and Drug Administration. We review recent advances in understanding of cGVHD pathophysiology and new approaches for the prevention and treatment of cGVHD.
Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the ...hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
Abstract Recently, targeted degradation has emerged as a powerful therapeutic modality. Relying on “event-driven” pharmacology, proteolysis targeting chimeras (PROTACs) can degrade targets and are ...superior to conventional inhibitors against undruggable proteins. Unfortunately, PROTAC discovery is limited by warhead scarcity and laborious optimization campaigns. To address these shortcomings, analogous protein-based heterobifunctional degraders, known as bioPROTACs, have been developed. Compared to small-molecule PROTACs, bioPROTACs have higher success rates and are subject to fewer design constraints. However, the membrane impermeability of proteins severely restricts bioPROTAC deployment as a generalized therapeutic modality. Here, we present an engineered bioPROTAC template able to complex with cationic and ionizable lipids via electrostatic interactions for cytosolic delivery. When delivered by biocompatible lipid nanoparticles, these modified bioPROTACs can rapidly degrade intracellular proteins, exhibiting near-complete elimination (up to 95% clearance) of targets within hours of treatment. Our bioPROTAC format can degrade proteins localized to various subcellular compartments including the mitochondria, nucleus, cytosol, and membrane. Moreover, substrate specificity can be easily reprogrammed, allowing modular design and targeting of clinically-relevant proteins such as Ras, Jnk, and Erk. In summary, this work introduces an inexpensive, flexible, and scalable platform for efficient intracellular degradation of proteins that may elude chemical inhibition.
Climate change is altering ecological systems throughout the world. Managing these systems in a way that ignores climate change will likely fail to meet management objectives. The uncertainty in ...projected climate-change impacts is one of the greatest challenges facing managers attempting to address global change. In order to select successful management strategies, managers need to understand the uncertainty inherent in projected climate impacts and how these uncertainties affect the outcomes of management activities. Perhaps the most important tool for managing ecological systems in the face of climate change is active adaptive management, in which systems are closely monitored and management strategies are altered to address expected and ongoing changes. Here, we discuss the uncertainty inherent in different types of data on potential climate impacts and explore climate projections and potential management responses at three sites in North America. The Central Valley of California, the headwaters of the Klamath River in Oregon, and the barrier islands and sounds of North Carolina each face a different set of challenges with respect to climate change. Using these three sites, we provide specific examples of how managers are already beginning to address the threat of climate change in the face of varying levels of uncertainty.
Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of ...genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.
The ability to deliver small protein scaffolds intracellularly could enable the targeting and inhibition of many therapeutic targets that are not currently amenable to inhibition with small-molecule ...drugs. Here, we report the engineering of small protein scaffolds with anionic polypeptides (ApPs) to promote electrostatic interactions with positively charged nonviral lipid-based delivery systems. Proteins fused with ApPs are either complexed with off-the-shelf cationic lipids or encapsulated within ionizable lipid nanoparticles for highly efficient cytosolic delivery (up to 90%). The delivery of protein inhibitors is used to inhibit two common proto-oncogenes, Ras and Myc, in two cancer cell lines. This report demonstrates the feasibility of combining minimally engineered small protein scaffolds with tractable nanocarriers to inhibit intracellular proteins that are generally considered “undruggable” with current small molecule drugs and biologics.
Objectives
Disaster workers are at elevated risk for mental health problems as a result of trauma exposures during response efforts. One possible way to prevent mental health problems is to build-up ...coping resources that promote resilience to the effects of disaster work. The primary aim of this study was to evaluate the efficacy of a resilience building workshop, the Disaster Worker Resiliency Training Program (DWRT), in disaster workers previously exposed to Hurricane Sandy.
Methods
Disaster workers (
N
= 167) were randomly assigned to the DWRT workshop (
n
= 78) or a waitlist (
n
= 89). Workers completed self-report measures on healthy lifestyle behaviors, perceived stress, depression, and Posttraumatic Stress Disorder (PTSD) symptoms at baseline and 3-month follow-up. They also completed a measure assessing subsequent trauma-exposure between the baseline and 3-month post-intervention.
Results
Participants in the workshop condition, as compared to those in a waitlist control, reported significantly greater improvements from pre-intervention (T1) to 3-month follow-up (T2) in healthy lifestyle behaviors (
η
2
= .03;
p
= .03), stress management (
η
2
= .03,
p
= .04), and spiritual growth (
η
2
= .03,
p
= .02). Among participants reporting subsequent trauma exposures between T1 and T2 (
n
= 101), participants in the waitlist condition, were more likely to report significant increases in perceived stress (
η
2
= .07,
p
< .01), PTSD (
η
2
= .05,
p
= .03), and depression (
η
2
= .07,
p
< .01) symptoms.
Conclusions
Participation in the resilience workshop promoted engagement in positive health behaviors and reduced the incidence of mental health symptoms, especially when administered prior to a repeat trauma exposure. Further research is needed to evaluate the long-term health effects of participation in the program.
Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare ...aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia.
Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses. bNAb specificities were studied by ELISA using mutated gp120, neutralization assays with mutated viruses, and peptide competition. Epitope specificities were also elucidated from the serum pattern of neutralization against a panel of diverse HIV-1 isolates.
Broadly neutralizing sera were found among 9.3% LTNPs, both elite (7%) and viremic controllers (14%). Within the broadly neutralizing sera, CD4 binding site antibodies were detected by ELISA in 4/12 LTNPs (33%), and 16/33 of TPs (48%). Anti-MPER antibodies were detected in 6/12 LTNPs (50%) and 14/33 TPs (42%) whereas glycan-dependent HIV-1 bNAbs were more frequent in LTNPs (11/12, 92%) as compared to TPs (12/33, 36%). A good concordance between standard serum mapping and neutralization-based mapping was observed.
LTNPs, both viremic and elite controllers, showed broad humoral immune responses against HIV-1, including activity against many major epitopes involved in bNAbs-mediated protection.
Abstract
In the midst of widespread community transmission of coronavirus disease 2019 (COVID-19) in New York, residents have sought information about COVID-19. We analyzed trends in New York State ...(NYS) and New York City (NYC) data to quantify the extent of COVID-19-related queries. Data on the number of 311 calls in NYC, Google Trend data on the search term ‘Coronavirus’ and information about trends in COVID-19 cases in NYS and the USA were compiled from multiple sources. There were 1228 994 total calls to 311 between 22 January 2020 and 22 April 2020, with 50 845 calls specific to COVID-19 in the study period. The proportion of 311 calls related to COVID-19 increased over time, while the ‘interest over time’ of the search term ‘Coronavirus’ has exponentially increased since the end of February 2020. It is vital that public health officials provide clear and up-to-date information about protective measures and crucial communications to respond to information-seeking behavior across NYC.
Pulmonary light chain deposition disease is a rare entity characterized by immunoglobulin deposition within the lung parenchyma with pathologic features distinct from pulmonary amyloidosis. Here, the ...authors present the clinical presentation, associations, and radiologic features of pulmonary light chain deposition disease in a series of 4 patients as well as discuss the distinctions from amyloidosis. The present case series highlights the frequent presence of both cysts and nodules at CT. Clinically, lymphoma and/or autoimmune disease are often associated.
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