Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial.

Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy.

Accelerating Parkinson's Disease drug development with federated learning approaches.

Parkinson's Disease is a progressive neurodegenerative disorder afflicting almost 12 million people. Increased understanding of its complex and heterogenous disease pathology, etiology and symptom manifestations has resulted in the need to design, capture and interrogate substantial clinical datasets. Herein we advocate how advances in the deployment of artificial intelligence models for Federated Data Analysis and Federated Learning can help spearhead coordinated and sustainable approaches to address this grand challenge.

A PROTAC degrader suppresses oncogenic functions of PTK6 inducing apoptosis of breast cancer cells.

Protein tyrosine kinase 6 (PTK6), a non-receptor tyrosine kinase, is an oncogenic driver in many tumor types. However, agents that therapeutically target PTK6 are lacking. Although several PTK6 kinase inhibitors have been developed, none have been clinically translated, which may be due to kinase-independent functions that compromise their efficacy.

Enantioselective synthesis of chiral α,α-dialkyl indoles and related azoles by cobalt-catalyzed hydroalkylation and regioselectivity switch.

General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp)-C(sp) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles.

Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade.

Backgrounds: Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of an immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types.

The association of long-term trajectories of BMI, its variability, and metabolic syndrome: a 30-year prospective cohort study.

Background: Limited data exists on how early-life weight changes relate to metabolic syndrome (MetS) risk in midlife. This study examines the association between long-term trajectories of body mass index (BMI), its variability, and MetS risk in Chinese individuals.

Methods: In the Hanzhong Adolescent Hypertension study (March 10, 1987-June 3, 2017), 1824 participants with at least five BMI measurements from 1987 to 2017 were included.

Application of synthetic lipid droplets in metabolic diseases.

Background: The study and synthesis of membrane organelles are becoming increasingly important, not only as simplified cellular models for corresponding molecular and metabolic studies but also for applications in synthetic biology of artificial cells and drug delivery vehicles. Lipid droplets (LDs) are central organelles in cellular lipid metabolism and are involved in almost all metabolic processes. Multiple studies have also demonstrated a high correlation between LDs and metabolic diseases.

Non-canonical amino acid incorporation into AAV5 capsid enhances lung transduction in mice.

Gene therapy using recombinant adeno-associated virus (rAAV) relies on safe, efficient, and precise gene delivery that is largely dependent on the AAV capsid. The proteinaceous capsid is highly amenable to engineering using a variety of approaches, and most resulting capsids carry substitutions or insertions comprised of natural amino acids. Here, we incorporated a non-canonical amino acid (ncAA), Nε-2-azideoethyloxycarbonyl-L-lysine (also known as NAEK), into the AAV5 capsid using genetic code expansion, and serendipitously found that several NAEK-AAV5 vectors transduced various cell lines more efficiently than the parental rAAV5.

Achieving ideal transistor characteristics in conjugated polymer semiconductors.

Organic thin-film transistors (OTFTs) with ideal behavior are highly desired, because nonideal devices may overestimate the intrinsic property and yield inferior performance in applications. In reality, most polymer OTFTs reported in the literature do not exhibit ideal characteristics. Supported by a structure-property relationship study of several low-disorder conjugated polymers, here, we present an empirical selection rule for polymer candidates for textbook-like OTFTs with high reliability factors (100% for ideal transistors).

Challenges and opportunities for modeling aging and cancer.

Age is among the main risk factors for cancer, and any cancer study in adults is faced with an aging tissue and organism. Yet, pre-clinical studies are carried out using young mice and are not able to address the impact of aging and associated comorbidities on disease biology and treatment outcomes. Here, we discuss the limitations of current mouse cancer models and suggest strategies for developing novel models to address these major gaps in knowledge and experimental approaches.

Theoretically Revealing the Response of Intermolecular Vibration Energy Transfer and Decomposition Process of the DNTF System to Electric Fields Using Two-Dimensional Infrared Spectra.

The external electric field (E-field), which is an important stimulus, can change the decomposition mechanism and sensitivity of energetic materials. As a result, understanding the response of energetic materials to external E-fields is critical for their safe use. Motivated by recent experiments and theories, the two-dimensional infrared (2D IR) spectra of 3,4-bis (3-nitrofurazan-4-yl) furoxan (DNTF), which has a high energy, a low melting point, and comprehensive properties, were theoretically investigated.

Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.

Background: The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations.

Methods: We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone.

First report of leaf blight caused by on wheat in China.

Wheat ( L.) is the main grain crop in Ningxia Hui Autonomous Region, China. A new leaf blight disease of wheat was observed in many wheat fields in Yinchuan City and Wuzhong City of Ningxia during 2020-2021.

Multicenter Study for the Treatment of Sidewall versus Bifurcation Intracranial Aneurysms with Use of Woven EndoBridge (WEB).

Background The Woven EndoBridge (WEB) device was explicitly designed for wide-neck intracranial bifurcation aneurysms. Small-scale reports have evaluated the off-label use of WEB devices for the treatment of sidewall aneurysms, with promising outcomes. Purpose To compare the angiographic and clinical outcomes of the WEB device for the treatment of sidewall aneurysms compared with the treatment of bifurcation aneurysms.

Shear-Thinning and Temperature-Dependent Viscosity Relationships of Contemporary Ocular Lubricants.

Purpose: To evaluate the shear viscosity of contemporary, commercially available ocular lubricants at various shear rates and temperatures and to derive relevant mathematical viscosity models that are impactful for prescribing and developing eye drops to treat dry eye disease.

Methods: The shear viscosity of 12 ocular lubricants was measured using a rheometer and a temperature-controlled bath at clinically relevant temperatures at which users may experience exposure to the drops (out of the refrigerator [4.3°C]; room temperature [24.

Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2.

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen.

Structural and Dynamic Disorder, Not Ionic Trapping, Controls Charge Transport in Highly Doped Conducting Polymers.

Doped organic semiconductors are critical to emerging device applications, including thermoelectrics, bioelectronics, and neuromorphic computing devices. It is commonly assumed that low conductivities in these materials result primarily from charge trapping by the Coulomb potentials of the dopant counterions. Here, we present a combined experimental and theoretical study rebutting this belief.

Evaluation of Clinical, Gram Stain, and Microbiological Cure Outcomes in Men Receiving Azithromycin for Acute Nongonococcal Urethritis: Discordant Cures Are Associated With Mycoplasma genitalium Infection.

Background: In men with nongonococcal urethritis (NGU), clinicians and patients rely on clinical cure to guide the need for additional testing/treatment and when to resume sex, respectively; however, discordant clinical and microbiological cure outcomes do occur. How accurately clinical cure reflects microbiological cure in specific sexually transmitted infections (STIs) is unclear.

Methods: Men with NGU were tested for Neisseria gonorrhoeae, Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis, urethrotropic Neisseria meningitidis ST-11 clade strains, and Ureaplasma urealyticum (UU).

Comparative assessment of reported symptoms of influenza, respiratory syncytial virus, and human metapneumovirus infection during hospitalization and post-discharge assessed by Respiratory Intensity and Impact Questionnaire.

Background: The hospitalized acute respiratory tract infection (HARTI) study used the Respiratory Intensity and Impact Questionnaire (RiiQ™) Symptom Scale, derived from FluiiQ™, to assess and compare the burden of respiratory infection symptoms for patients with influenza, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) infection, with or without core risk factors (CRF) (age ≥65; chronic heart, renal, obstructive pulmonary disease; asthma).

Methods: This was a prospective cohort study in adult patients hospitalized with acute respiratory tract infection (40 centers, 12 countries) during two consecutive influenza/RSV/hMPV seasons (2017-2019). The RiiQ™ Symptom Scale and EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) were assessed by interview at two timepoints during hospitalization and at 1, 2, and 3 months post-discharge.

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation.

Development of Sequence-Tagged Site Marker Set for Identification of J, J, and St Sub-genomes of in Wheat Background.

(2 = 6 = 42, JJJJStSt) is one of the important resources for the wheat improvement. So far, a few ()-specific molecular markers have been reported, but the number is far from enough to meet the need of identifying alien fragments in wheat- hybrids. In this study, 5,877,409 contigs were assembled using the genotyping-by-sequencing (GBS) data.