Cathepsin B Nuclear Flux in a DNA-Guided "Antinuclear Missile" Cancer Therapy.

Some antinuclear antibodies (ANAs) bind extracellular nucleic acids released into tumor environments and are pulled into the nuclei of live cancer cells through nucleoside salvage pathways, independent of tumor-specific surface antigens. Here we show that ANA nuclear penetration induces nuclear flux by the lysosomal protease cathepsin B and leverage this mechanism to design an antinuclear antibody-drug conjugate (ANADC) with cathepsin B-labile drug linker. The ANADC targets nucleic acid exhaust from necrotic tumors and crosses membrane barriers through nucleoside salvage as a DNA-seeking and tumor agnostic "antinuclear missile" cancer therapy.

Nuclear-penetrating scleroderma autoantibody inhibits topoisomerase 1 cleavage complex formation.

The contributions of anti-Topoisomerase 1 (Top1) autoantibodies to the pathophysiology of diffuse cutaneous systemic sclerosis (dcSSc), the most aggressive scleroderma subtype, are unknown. Top1 catalyzes DNA relaxation and unwinding in cell nuclei, a site previously considered inaccessible to antibodies. The discovery of autoantibodies in systemic lupus erythematosus that penetrate nuclei and inhibit DNA repair raised the possibility that nuclear-penetrating autoantibodies contribute to mechanisms of autoimmunity.

How do we leverage data through replication and warehousing to meet blood collection and transfusion service needs.

Background: With the widespread adoption of Blood Establishment Computer Systems and other Blood Collection and Transfusion Service (BCTS) clinical information systems (CIS), electronic blood donor, product, and patient data are now routinely required for clinical, regulatory, operational, and quality needs. That data are often not readily accessible for such secondary use within CIS databases, particularly for applications with significant data availability requirements such as machine learning and artificial intelligence. Data replication provides one avenue by which CIS data can be made more readily available.

Cellular protection from HO toxicity by Fv-Hsp70: protection via catalase and gamma-glutamyl-cysteine synthase.

Heat shock proteins (HSPs), especially Hsp70 (HSPA1), have been associated with cellular protection from various cellular stresses including heat, hypoxia-ischemia, neurodegeneration, toxins, and trauma. Endogenous HSPs are often synthesized in direct response to these stresses but in many situations are inadequate in protecting cells. The present study addresses the transduction of Hsp70 into cells providing protection from acute oxidative stress by HO.

Preliminary dosimetric comparison between fixed and rotating source stereotactic radiosurgery systems.

Purpose: The Akesis Galaxy RTi (AK) is a novel rotational Co-based cranial stereotactic radiosurgery (SRS) system. While similar systems have been compared against the fixed-source Leksell Gamma Knife (GK) system using stylized phantoms, dosimetric plan quality with realistic anatomy has yet to be characterized for this or any other rotating system versus GK. This study aims to benchmark AK dosimetric performance against GK by retrospectively replanning previously-treated GK patients at our institution.

Inhibition of NETosis by a Nuclear-Penetrating Anti-DNA Autoantibody.

Nuclear-penetrating anti-DNA autoantibodies have therapeutic potential as delivery agents and in targeting DNA and the DNA damage response (DDR). Derivatives of such Abs have advanced to human testing in genetic disease and are in preparation for oncology clinical trials. DNA release associated with neutrophil extracellular traps (NETs) contributes to immunity, inflammation, and the pathophysiology of multiple diseases.

Defective Early B Cell Tolerance Checkpoints in Patients With Systemic Sclerosis Allow the Production of Self Antigen-Specific Clones.

Objective: Early selection steps preventing autoreactive naive B cell production are often impaired in patients with autoimmune diseases, but central and peripheral B cell tolerance checkpoints have not been assessed in patients with systemic sclerosis (SSc). This study was undertaken to characterize early B cell tolerance checkpoints in patients with SSc.

Methods: Using an in vitro polymerase chain reaction-based approach that allows the expression of recombinant antibodies cloned from single B cells, we tested the reactivity of antibodies expressed by 212 CD19+CD21 CD10+IgM CD27- new emigrant/transitional B cells and 190 CD19+CD21+CD10-IgM+CD27- mature naive B cells from 10 patients with SSc.

ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody.

The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response.

Impact of tissue heterogeneity correction on Gamma Knife stereotactic radiosurgery of acoustic neuromas.

Purpose/objectives: Treatment planning systems (TPS) for Gamma Knife stereotactic radiosurgery (GK-SRS) include TMR10 algorithms, which assumes tissue homogeneity equivalent to water, and collapsed-cone convolutional (CCC) algorithms, which accounts for tissue inhomogeneity. This study investigated dosimetric differences between TMR10 and CCC TPS for acoustic neuromas (ANs) treated with GK-SRS.

Materials/methods: A retrospective review of 56 AN treated with GK-SRS was performed.

LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy.

Breast cancer brain metastasis (BCBM) is a devastating disease. Radiation therapy remains the mainstay for treatment of this disease. Unfortunately, its efficacy is limited by the dose that can be safely applied.

Multi-institutional retrospective review of stereotactic radiosurgery for brain metastasis in patients with small cell lung cancer without prior brain-directed radiotherapy.

Patients with small cell lung cancer (SCLC) brain metastasis (BM) typically receive whole brain radiotherapy (WBRT) as data regarding upfront radiosurgery (SRS) in this setting are sparse. Patients receiving SRS for SCLC BM without prior brain radiation were identified at three U.S.

Potential for large-scale CO removal via enhanced rock weathering with croplands.

Enhanced silicate rock weathering (ERW), deployable with croplands, has potential use for atmospheric carbon dioxide (CO) removal (CDR), which is now necessary to mitigate anthropogenic climate change. ERW also has possible co-benefits for improved food and soil security, and reduced ocean acidification. Here we use an integrated performance modelling approach to make an initial techno-economic assessment for 2050, quantifying how CDR potential and costs vary among nations in relation to business-as-usual energy policies and policies consistent with limiting future warming to 2 degrees Celsius.

Cancer and Systemic Lupus Erythematosus.

Systemic lupus erythematosus is associated with a small overall increased cancer risk compared with the general population. This risk includes a 4-fold increased risk of non-Hodgkin lymphoma, but a decreased risk of other cancers (such as breast cancer). The pathophysiology underlying the increased risk of hematologic cancer is not fully understood, but many potential mechanisms have been proposed, including dysfunction of the tumor necrosis factor and other pathways.

A New Bronchodilator Response Grading Strategy Identifies Distinct Patient Populations.

A positive bronchodilator response (BDR) according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines require both 200 ml and 12% increase in forced expiratory volume in 1 second (FEV) or forced vital capacity (FVC) after bronchodilator inhalation. This dual criterion is insensitive in those with high or low FEV. To establish BDR criteria with volume or percentage FEV change.

Publisher Correction: Farming with crops and rocks to address global climate, food and soil security.

In the version of this Perspective originally published, 'acidification' was incorrectly spelt as 'adification' in Fig. 4. This has now been corrected.

Incidence of radiographically occult nodal metastases in HPV+ oropharyngeal carcinoma: Implications for reducing elective nodal coverage.

Purpose: Initial deescalation studies for human papilloma virus (HPV)-positive driven oropharyngeal squamous cell carcinomas (HPV+ OPSCC) altered radiation therapy dose or the systemic agent used. Newer trials examine the disease control achieved with a reduced elective nodal field. We examined patterns of nodal involvement in patients with HPV+ OPSCC with a focus on implications for radiation field design for treatment deescalation.

Streamlining cardiopulmonary exercise testing for use as a screening and tracking tool in primary care.

Cardiopulmonary exercise testing (CPET) using a spectrum of different approaches demonstrates usefulness for objectively assessing patient disease severity in clinical and research settings. Still, an absence of trained specialists and/or improper data interpretation techniques can pose major limitations to the effective use of CPET for the clinical classification of patients. This study aimed to test an automated disease likelihood scoring algorithm system based on cardiopulmonary responses during a simplified step-test protocol.

Reliability and Physiological Interpretation of Pulmonary Gas Exchange by "Circulatory Equivalents" in Chronic Heart Failure.

Background: Peak ratios of pulmonary gas-exchange to ventilation during exercise (V˙O2/V˙E and V˙CO2/V˙E, termed "circulatory equivalents") are sensitive to heart failure (HF) severity, likely reflecting low and/or poorly distributed pulmonary perfusion. We tested whether peak V˙O2/V˙E and V˙CO2/V˙E would: (1) distinguish HF patients from controls; (2) be independent of incremental exercise protocol; and (3) correlate with lactate threshold (LT) and ventilatory compensation point (VCP), respectively.

Methods And Results: Twenty-four HF patients (61±11 years) with reduced ejection fraction (31±8%) and 11 controls (63±7 years) performed ramp-incremental cycle ergometry.

Farming with crops and rocks to address global climate, food and soil security.

The magnitude of future climate change could be moderated by immediately reducing the amount of CO entering the atmosphere as a result of energy generation and by adopting strategies that actively remove CO from it. Biogeochemical improvement of soils by adding crushed, fast-reacting silicate rocks to croplands is one such CO-removal strategy. This approach has the potential to improve crop production, increase protection from pests and diseases, and restore soil fertility and structure.

Re-engineering and evaluation of anti-DNA autoantibody 3E10 for therapeutic applications.

A key challenge in the development of novel chemotherapeutics is the design of molecules capable of selective toxicity to cancer cells. Antibodies have greater target specificity compared to small molecule drugs, but most are unable to penetrate cells, and predominantly target extracellular antigens. A nuclear-penetrating anti-DNA autoantibody isolated from the MRL/lpr lupus mouse model, 3E10, preferentially localizes to tumors, inhibits DNA repair, and selectively kills cancer cells with defects in DNA repair.

Smoking Is the Most Significant Modifiable Lung Cancer Risk Factor in Systemic Lupus Erythematosus.

Objective: To assess lung cancer risk in systemic lupus erythematosus (SLE), relative to demographics, drug exposures, smoking, and disease activity.

Methods: We analyzed data from 14 SLE cohorts. We calculated adjusted HR estimates for lung cancer in SLE, relative to demographics, smoking, time-dependent medication exposures, and cumulative disease activity [mean adjusted SLE Disease Activity Index (SLEDAI) scores].

Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids.

Background: Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.

Methods: A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases.

Death and Dialysis After Transcatheter Aortic Valve Replacement: An Analysis of the STS/ACC TVT Registry.

Objectives: The authors sought to elucidate the true incidence of renal replacement therapy (RRT) after transcatheter aortic valve replacement (TAVR).

Background: There is a wide discrepancy in the reported rate of RRT after TAVR (1.4% to 40%).

Prosthetic mitral valve paravalvular leak: A problem that requires dexterity.

Prosthetic valve paravalvular leak (PVL) is a known and relatively common complication of surgical valve replacement, which may lead to significant morbidity. Patients with significant mitral valve replacement (MVR) PVL typically present with symptoms of heart failure and elevated filling pressures or with hemolytic anemia. Percutaneous closure of these leaks has become the preferred therapy.

Algorithm for Predicting Disease Likelihood From a Submaximal Exercise Test.

We developed a simplified automated algorithm to interpret noninvasive gas exchange in healthy subjects and patients with heart failure (HF, n = 12), pulmonary arterial hypertension (PAH, n = 11), chronic obstructive lung disease (OLD, n = 16), and restrictive lung disease (RLD, n = 12). They underwent spirometry and thereafter an incremental 3-minute step test where heart rate and SpO respiratory gas exchange were obtained. A custom-developed algorithm for each disease pathology was used to interpret outcomes.