Development of a radiolabeled site-specific single-domain antibody positron emission tomography probe for monitoring PD-L1 expression in cancer

Despite advances in immunotherapy for the treatment of cancers,not all patients can benefit from programmed cell death ligand 1(PD-L1)immune checkpoint blockade therapy.Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level;hence,accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects.Therefore,based on the high affinity antibody Nb109,a new site-specifically radiolabeled tracer,^(68)Ga-NODA-cysteine,aspartic acid,and valine(CDV)-Nb109,was designed and synthesized to accurately monitor PD-L1 expression.The tracer ^(68)Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95%and radiochemical purity of 97%.It showed high affinity for PD-L1 with a dissociation constant of 12.34±1.65 nM.Both the cell uptake assay and positron emission tomography(PET)imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells.Meanwhile,dynamic PET imaging of a NCI-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression,allowing timely interventional immunotherapy.In conclusion,this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.

A Hybrid Biofuel and Triboelectric Nanogenerator for Bioenergy Harvesting

Various types of energy exist everywhere around us,and these energies can be harvested from multiple sources to power micro-/nanoelectronic system and even personal electronic products.In this work,we proposed a hybrid energy-harvesting system(HEHS)for potential in vivo applications.The HEHS consisted of a triboelectric nanogenerator and a glucose fuel cell for simultaneously harvesting biomechanical energy and biochemical energy in simulated body fluid.These two energy-harvesting units can work individually as a single power source or work simultaneously as an integrated system.This design strengthened the flexibility of harvesting multiple energies and enhanced corresponding electric output.Compared with any individual device,the integrated HEHS outputs a superimposed current and has a faster charging rate.Using the harvested energy,HEHS can power a calculator or a green light-emitting diode pattern.Considering the widely existed biomechanical energy and glucose molecules in the body,the developed HEHS can be a promising candidate for building in vivo self-powered healthcare monitoring system.

Correction to:A Hybrid Biofuel and Triboelectric Nanogenerator for Bioenergy Harvesting

In the original publication,the authors’contribution is missing in the acknowledgment section.The correct acknowledgement is provided in this correction.Also,in Fig.4,the second(c)after figure(d)should be read as(e).In Fig.5(i),the Y-axis label“Current(μA)”should be read as“Voltage”.

Expert consensus on the diagnosis and treatment of solid tumors with BRAF mutations

The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signaling pathway,which promotes cell proliferation,inhibits cell apoptosis,and ultimately contributes to the occurrence and development of cancer.BRAF mutations are widely present in various cancers,including malignant melanoma,thyroid cancer,colorectal cancer,non-small cell lung cancer,and hairy cell leukemia,among others.BRAF is an important target for the treatment of various solid tumors,and targeted combination therapies,represented by BRAF inhibitors,have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors.

PIN FORMED 2 Modulates the Transport of Arsenite in Arabidopsis thaliana

Arsenic contamination is a major environmental issue,as it may lead to serious health hazard.The reduced trivalent formof inorganic arsenic,arsenite,is in generalmore toxic to plants comparedwith the fully oxidized pentavalent arsenate.Theuptakeof arsenite inplants hasbeenshown tobemediatedthrough a large subfamily of plant aquaglyceroporins,nodulin 26-like intrinsic proteins(NIPs).However,the efflux mechanisms,as well as themechanismof arsenite-induced root growth inhibition,remain poorly understood.Usingmolecular physiology,synchrotron imaging,and root transport assay approaches,we show that the cellular transport of trivalent arsenicals inArabidopsis thalianais stronglymodulatedbyPINFORMED2(PIN2)auxin efflux transporter.Root transport assay using radioactive arsenite,X-ray fluorescence imaging(XFI)coupled with X-ray absorption spectroscopy(XAS),and inductively coupled plasma mass spectrometry analysis revealed that pin2 plants accumulate higher concentrations of arsenite in roots comparedwith the wild-type.At the cellular level,arsenite specifically targets intracellular sorting of PIN2 and thereby alters the cellular auxin homeostasis.Consistently,loss of PIN2 function results in arsenite hypersensitivity in roots.XFI coupled with XAS further revealed that loss of PIN2 function results in specific accumulation of arsenical species,but not the other metals such as iron,zinc,or calcium in the root tip.Collectively,these results suggest that PIN2 likely functions as an arsenite efflux transporter for the distribution of arsenical species in planta.

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic cells.Brain TSPO expression is relatively low under physiological conditions,but is upregulated in response to glial cell activation.As the primary index of neuroinflammation,TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases,including Alzheimer’s disease(AD),amyotrophic lateral sclerosis(ALS),Parkinson’s disease(PD),multiple sclerosis(MS),major depressive disorder(MDD)and obsessive compulsive disorder(OCD).In this context,numerous TSPO-targeted positron emission tomography(PET)tracers have been developed.Among them,several radioligands have advanced to clinical research studies.In this review,we will overview the recent development of TSPO PET tracers,focusing on the radioligand design,radioisotope labeling,pharmacokinetics,and PET imaging evaluation.Additionally,we will consider current limitations,as well as translational potential for future application of TSPO radiopharmaceuticals.This review aims to not only present the challenges in current TSPO PET imaging,but to also provide a new perspective on TSPO targeted PET tracer discovery efforts.Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.

Capsaicin restores sodium iodine symportermediated radioiodine uptake through bypassing canonical TSH–TSHR pathway in anaplastic thyroid carcinoma cells

Anaplastic thyroid cancer(ATC)is a rare but highly lethal disease.ATCs are resistant to standard therapies and are extremely difficult to manage.The stepwise cell dedifferentiation results in the impairment of the iodine-metabolizing machinery and the infeasibility of radioiodine treatment in ATC.Hence,reinducing iodine-metabolizing gene expression to restore radioiodine avidity is considered as a promising strategy to fight against ATC.In the present study,capsaicin(CAP),a natural potent transient receptor potential vanilloid type 1(TRPV1)agonist,was discovered to reinduce ATC cell differentiation and to increase the expression of thyroid transcription factors(TTFs including TTF-1,TTF-2,and PAX8)and iodine-metabolizing proteins,including thyroidstimulating hormone receptor(TSHR),thyroid peroxidase,and sodium iodine symporter(NIS),in two ATC cell lines,8505C and FRO.Strikingly,CAP treatment promoted NIS glycosylation and its membrane trafficking,resulting in a significant enhancement of radioiodine uptake of ATC cells in vitro.Mechanistically,CAP-activated TRPV1 channel and subsequently triggered Ca2þinflux,cyclic adenosine monophosphate(cAMP)generation,and cAMP-responsive element-binding protein(CREB)signal activation.Next,CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.Moreover,the TRPV1 antagonist CPZ,the calcium chelator BAPTA,and the PKA inhibitor H-89 effectively alleviated the redifferentiation exerted by CAP,demonstrating that CAP might improve radioiodine avidity through the activation of the TRPV1–Ca2þ/cAMP/PKA/CREB signaling pathway.In addition,our study indicated that CAP might trigger a novel cascade to redifferentiate ATC cells and provide unprecedented opportunities for radioiodine therapy in ATC,bypassing canonical TSH–TSHR pathway.