PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.

Background: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies).

Inhibition of Hmbox1 Promotes Cardiomyocyte Survival and Glucose Metabolism Through Gck Activation in Ischemia/Reperfusion Injury.

Background: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored.

Increased Ca Transient Underlies RyR2-Related Left Ventricular Noncompaction.

Background: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M, has recently been linked to a new cardiac disorder termed RyR2 Ca release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M loss-of-function mutation on cardiac structure and function.

Clonal hematopoiesis is associated with protection from Alzheimer's disease.

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD.

Evaluation of T cell responses to naturally processed variant SARS-CoV-2 spike antigens in individuals following infection or vaccination.

Most existing studies characterizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses are peptide based. This does not allow evaluation of whether tested peptides are processed and presented canonically. In this study, we use recombinant vaccinia virus (rVACV)-mediated expression of SARS-CoV-2 spike protein and SARS-CoV-2 infection of angiotensin-converting enzyme (ACE)-2-transduced B cell lines to evaluate overall T cell responses in a small cohort of recovered COVID-19 patients and uninfected donors vaccinated with ChAdOx1 nCoV-19.

Induction and Maintenance Treatment With Upadacitinib Improves Health-Related Quality of Life in Patients With Moderately to Severely Active Ulcerative Colitis: Phase 3 Study Results.

Background: We evaluated the health-related quality of life (HRQoL) benefits of upadacitinib (UPA) induction and maintenance treatment in a phase 3 study of patients with ulcerative colitis (UC) across a broad range of patient-centered outcomes.

Methods: Patients received UPA 45 mg once daily or placebo as induction treatment for 8 weeks. Patients who achieved clinical response were rerandomized to receive once daily UPA 15 mg, 30 mg, or placebo as maintenance treatment for 52 weeks.

Evaluation of pembrolizumab monotherapy in patients with previously treated advanced salivary gland carcinoma in the phase 2 KEYNOTE-158 study.

Aim: We evaluated pembrolizumab monotherapy in patients with advanced salivary gland carcinoma on the phase 2 KEYNOTE-158 study (NCT02628067).

Methods: Eligible patients had histologically/cytologically confirmed advanced salivary gland carcinoma with prior failure or intolerance to standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

The road to biologics in patients with hidradenitis suppurativa: a nationwide drug utilization study.

Background: Prolonged systemic antibiotic treatment is often a part of management of hidradenitis suppurativa (HS). Although biologic therapies are now available, the patient's treatment journey leading to biologic therapy is unclear.

Objectives: To examine treatment patterns and duration of systemic treatment use in patients with HS preceding biologic therapy.

Evidence for a New Structure in the J/ψp and J/ψp[over ¯] Systems in B_{s}^{0}→J/ψpp[over ¯] Decays.

An amplitude analysis of flavor-untagged B_{s}^{0}→J/ψpp[over ¯] decays is performed using a sample of 797±31 decays reconstructed with the LHCb detector. The data, collected in proton-proton collisions between 2011 and 2018, correspond to an integrated luminosity of 9  fb^{-1}. Evidence for a new structure in the J/ψp and J/ψp[over ¯] systems with a mass of 4337_{-4}^{+7} _{-2}^{+2}  MeV and a width of 29_{-12}^{+26} _{-14}^{+14}  MeV is found, where the first uncertainty is statistical and the second systematic, with a significance in the range of 3.

Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium Against Ischemia-Reperfusion Injury in Canis.

[Figure: see text].

Observation of New Resonances Decaying to J/ψK^{+} and J/ψϕ.

The first observation of exotic states with a new quark content cc[over ¯]us[over ¯] decaying to the J/ψK^{+} final state is reported with high significance from an amplitude analysis of the B^{+}→J/ψϕK^{+} decay. The analysis is carried out using proton-proton collision data corresponding to a total integrated luminosity of 9  fb^{-1} collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. The most significant state, Z_{cs}(4000)^{+}, has a mass of 4003±6_{-14}^{+4}  MeV, a width of 131±15±26  MeV, and spin parity J^{P}=1^{+}, where the quoted uncertainties are statistical and systematic, respectively.

Sodium MR Neuroimaging.

Sodium MR imaging has the potential to complement routine proton MR imaging examinations with the goal of improving diagnosis, disease characterization, and clinical monitoring in neurologic diseases. In the past, the utility and exploration of sodium MR imaging as a valuable clinical tool have been limited due to the extremely low MR signal, but with recent improvements in imaging techniques and hardware, sodium MR imaging is on the verge of becoming clinically realistic for conditions that include brain tumors, ischemic stroke, and epilepsy. In this review, we briefly describe the fundamental physics of sodium MR imaging tailored to the neuroradiologist, focusing on the basics necessary to understand factors that play into making sodium MR imaging feasible for clinical settings and describing current controversies in the field.

Observation of a New Excited Beauty Strange Baryon Decaying to Ξ_{b}^{-}π^{+}π^{-}.

The Ξ_{b}^{-}π^{+}π^{-} invariant mass spectrum is investigated with an event sample of proton-proton collisions at sqrt[s]=13  TeV, collected by the CMS experiment at the LHC in 2016-2018 and corresponding to an integrated luminosity of 140  fb^{-1}. The ground state Ξ_{b}^{-} is reconstructed via its decays to J/ψΞ^{-} and J/ψΛK^{-}. A narrow resonance, labeled Ξ_{b}(6100)^{-}, is observed at a Ξ_{b}^{-}π^{+}π^{-} invariant mass of 6100.

Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS.

Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.

Anti-HSP47 siRNA lipid nanoparticle ND-L02-s0201 reverses interstitial pulmonary fibrosis in preclinical rat models.

ND-L02-s0201 is a lipid nanoparticle encapsulating an siRNA which inhibits expression of heat shock protein 47 (HSP47), a collagen-specific chaperone. Accumulated evidence demonstrates a close association between increased level of HSP47 and excessive accumulation of collagen in fibrotic diseases. Our objective was to test ND-L02-s0201 efficacy in preclinical lung fibrosis models and characterise the downstream histological and functional consequences of inhibiting the expression of HSP47.

Isotope tracing in adult zebrafish reveals alanine cycling between melanoma and liver.

The cell-intrinsic nature of tumor metabolism has become increasingly well characterized. The impact that tumors have on systemic metabolism, however, has received less attention. Here, we used adult zebrafish harboring BRAF-driven melanoma to study the effect of cancer on distant tissues.

Observation of a New Excited D_{s}^{+} Meson in B^{0}→D^{-}D^{+}K^{+}π^{-} Decays.

Using pp collision data corresponding to an integrated luminosity of 5.4  fb^{-1} collected with the LHCb detector at a center-of-mass energy of 13 TeV, the B^{0}→D^{-}D^{+}K^{+}π^{-} decay is studied. A new excited D_{s}^{+} meson is observed decaying into the D^{+}K^{+}π^{-} final state with large statistical significance.

Role of Intracardiac Defibrillation During the Ablation Procedure as a Predictor of Atrial Fibrillation Recurrence After Catheter Ablation.

Intracardiac defibrillation (IDF) is performed to restore sinus rhythm (SR) during radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). This study aimed to investigate the change in the IDF threshold before and after RFCA during the ablation procedure and determine whether the IDF threshold after RFCA was associated with the AF substrate and AF recurrence. A total of 141 consecutive patients with drug-refractory persistent AF (age 62.

Ca-CaM Dependent Inactivation of RyR2 Underlies Ca Alternans in Intact Heart.

Rationale: Ca alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca alternans remains undefined. Increasing evidence suggests that Ca alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca alternans are unknown.

How Will Machine Learning Inform the Clinical Care of Atrial Fibrillation?

Machine learning applications in cardiology have rapidly evolved in the past decade. With the availability of machine learning tools coupled with vast data sources, the management of atrial fibrillation (AF), a common chronic disease with significant associated morbidity and socioeconomic impact, is undergoing a knowledge and practice transformation in the increasingly complex healthcare environment. Among other advances, deep-learning machine learning methods, including convolutional neural networks, have enabled the development of AF screening pathways using the ubiquitous 12-lead ECG to detect asymptomatic paroxysmal AF in at-risk populations (such as those with cryptogenic stroke), the refinement of AF and stroke prediction schemes through comprehensive digital phenotyping using structured and unstructured data abstraction from the electronic health record or wearable monitoring technologies, and the optimization of treatment strategies, ranging from stroke prophylaxis to monitoring of antiarrhythmic drug (AAD) therapy.

Higher Doses Improve Walking Recovery During Stroke Inpatient Rehabilitation.

Background And Purpose: We investigated the effect of higher therapeutic exercise doses on walking during inpatient rehabilitation, typically commencing 1 to 4 weeks poststroke.

Methods: This phase II, blinded-assessor, randomized controlled trial recruited from 6 Canadian inpatient rehabilitation units, between 2014 and 2018. Subjects (n=75; 25/group) were randomized into: control (usual care) physical therapy: typically, 1 hour, 5 days/week; Determining Optimal Post-Stroke Exercise (DOSE1): 1 hour, 5 days/week, more than double the intensity of Control (based on aerobic minutes and walking steps); and DOSE2: 2 hours, 5 days/week, more than quadruple the intensity of Control, each for 4 weeks duration.

A thermally activated and highly miscible dopant for n-type organic thermoelectrics.

N-doping plays an irreplaceable role in controlling the electron concentration of organic semiconductors thus to improve performance of organic semiconductor devices. However, compared with many mature p-doping methods, n-doping of organic semiconductor is still of challenges. In particular, dopant stability/processability, counterion-semiconductor immiscibility and doping induced microstructure non-uniformity have restricted the application of n-doping in high-performance devices.