Innate type 2 immunity controls hair follicle commensalism by Demodex mites.

Demodex mites are commensal parasites of hair follicles (HFs). Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction, and aging, but mechanisms restricting Demodex outgrowth are not defined. Here, we show that control of mite HF colonization in mice required group 2 innate lymphoid cells (ILC2s), interleukin-13 (IL-13), and its receptor, IL-4Ra-IL-13Ra1. HF-associated ILC2s elaborated IL-13 that attenuated HFs and epithelial proliferation at anagen onset; in their absence, Demodex colonization led to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammation, leading to the loss of barrier function and HF exhaustion. Humans with rhinophymatous acne rosacea, an inflammatory condition associated with Demodex, had increased HF inflammation with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a key role for skin ILC2s and IL-13, which comprise an immune checkpoint that sustains cutaneous integrity and restricts pathologic infestation by colonizing HF mites.

Tissue signals imprint ILC2 identity with anticipatory function.

Group 2 innate lymphoid cells (ILC2s) are distributed systemically and produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Transcriptional profiling of ILC2s from different tissues, however, grouped ILC2s according to their tissue of origin, even in the setting of combined IL-25-, IL-33-receptor-, and TSLP-receptor-deficiency. Single-cell profiling confirmed a tissue-organizing transcriptome and identified ILC2 subsets expressing distinct activating receptors, including the major subset of skin ILC2s, which were activated preferentially by IL-18. Tissue ILC2 subsets were unaltered in number and expression in germ-free mice, suggesting that endogenous, tissue-derived signals drive the maturation of ILC2 subsets by controlling expression of distinct patterns of activating receptors, thus anticipating tissue-specific perturbations occurring later in life.

A tissue checkpoint regulates type 2 immunity.

Group 2 innate lymphoid cells (ILC2s) and CD4+ type 2 helper T cells (TH2 cells) are defined by their similar effector cytokines, which together mediate the features of allergic immunity. We found that tissue ILC2s and TH2 cells differentiated independently but shared overlapping effector function programs that were mediated by exposure to the tissue-derived cytokines interleukin 25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP). Loss of these three tissue signals did not affect lymph node priming, but abrogated the terminal differentiation of effector TH2 cells and adaptive lung inflammation in a T cell-intrinsic manner. Our findings suggest a mechanism by which diverse perturbations can activate type 2 immunity and reveal a shared local-tissue-elicited checkpoint that can be exploited to control both innate and adaptive allergic inflammation.

Tissue-Resident Group 2 Innate Lymphoid Cells Differentiate by Layered Ontogeny and In Situ Perinatal Priming.

The perinatal period is a critical window for distribution of innate tissue-resident immune cells within developing organs. Despite epidemiologic evidence implicating the early-life environment in the risk for allergy, temporally controlled lineage tracing of group 2 innate lymphoid cells (ILC2s) during this period remains unstudied. Using complementary fate-mapping approaches and reporters for ILC2 activation, we show that ILC2s appeared in multiple organs during late gestation like tissue macrophages, but, unlike the latter, a majority of peripheral ILC2 pools were generated de novo during the postnatal window. This period was accompanied by systemic ILC2 priming and acquisition of tissue-specific transcriptomes. Although perinatal ILC2s were variably replaced across tissues with age, the dramatic increases in tissue ILC2s following helminth infection were mediated through local expansion independent of de novo generation by bone marrow hematopoiesis. We provide comprehensive temporally controlled fate mapping of an innate lymphocyte subset with notable nuances as compared to tissue macrophage ontogeny.

Werner syndrome protein works as a dimer for unwinding and replication fork regression.

The determination of the oligomeric state of functional enzymes is essential for the mechanistic understanding of their catalytic activities. RecQ helicases have diverse biochemical activities, but it is still unclear how their activities are related to their oligomeric states. We use single-molecule multi-color fluorescence imaging to determine the oligomeric states of Werner syndrome protein (WRN) during its unwinding and replication fork regression activities. We reveal that WRN binds to a forked DNA as a dimer, and unwinds it without any change of its oligomeric state. In contrast, WRN binds to a replication fork as a tetramer, and is dimerized during activation of replication fork regression. By selectively inhibiting the helicase activity of WRN on specific strands, we reveal how the active dimers of WRN distinctly use the energy of ATP hydrolysis for repetitive unwinding and replication fork regression.

Recent progress and prospects of dimer and multimer acceptors for efficient and stable polymer solar cells.

High power conversion efficiency (PCE) and long-term stability are essential prerequisites for the commercialization of polymer solar cells (PSCs). Small-molecule acceptors (SMAs) are core materials that have led to recent, rapid increases in the PCEs of the PSCs. However, a critical limitation of the resulting PSCs is their poor long-term stability. Blend morphology degradation from rapid diffusion of SMAs with low glass transition temperatures (Tgs) is considered the main cause of the poor long-term stability of the PSCs. The recent emergence of oligomerized SMAs (OSMAs), composed of two or more repeating SMA units (i.e., dimerized and trimerized SMAs), has shown great promise in overcoming these challenges. This innovation in material design has enabled OSMA-based PSCs to reach impressive PCEs near 19% and exceptional long-term stability. In this review, we summarize the evolution of OSMAs, including their research background and recent progress in molecular design. In particular, we discuss the mechanisms for high PCE and stability of OSMA-based PSCs and suggest useful design guidelines for high-performance OSMAs. Furthermore, we reflect on the existing hurdles and future directions for OSMA materials towards achieving commercially viable PSCs with high PCEs and operational stabilities.

Nanostructured Molecular Packing of Polymer Films Formed on Water Surfaces.

In this study, we examined the nanostructured molecular packing and orientations of poly[[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)] (P(NDI2OD-T2)) films formed on water for the application of nanotechnology-based organic electronic devices. First, the nanoscale molecule-substrate interaction between the polymer and water was modulated by controlling the alkyl side chain length in NDI-based copolymers. Increasing alkyl side chain lengths induced a nanomorphological transition from face-on to edge-on orientation, confirmed by molecular dynamics simulations revealing nanostructural behavior. Second, the nanoscale intermolecular interactions of P(NDI2OD-T2) were controlled by varying the volume ratio of the high-boiling-point additive solvent in the binary solvent blends. As the additive solvent ratio increased, the nanostructured molecular orientation of the P(NDI2OD-T2) films on water changed remarkably from edge-on to bimodal with more face-on crystallites, thereby affecting charge transport. Our finding provides essential insights for precise nanoscale morphological control on water substrates, enabling the formation of high-performance polymer films for organic electronic devices.

High Efficiency Breathable Thermoelectric Skin Using Multimode Radiative Cooling/Solar Heating Assisted Large Thermal Gradient.

This study proposes a Janus structure-based stretchable and breathable thermoelectric skin with radiative cooling (RC) and solar heating (SH) functionalities for sustainable energy harvesting. The challenge of the wearable thermoelectric generator arises from the small temperature difference. Thus, this dual-sided structure maximizes the thermal gradient between the body and the surrounding environment, unlike the previous works that rather concentrate on the efficiency of the thermoelectric generator itself. The Janus structure allows the device to switch to the other mode, optimizing electricity generation from a given weather condition. For these functionalities, for the first time, boron nitride-polydimethylsiloxane (BP) and graphene nanoplatelet-polydimethylsiloxane (GP) nanofiber (NF) are developed as substrates. The BP NF generates the RC capability of ΔTcooling  = 4 °C, and the high solar absorbance of the GP NF enables it to be photothermally heated. The flip-overable thermoelectric skin (FoTES) achieves a maximum power output (Pmax ) of 5.73 µW cm-2 in RC mode, surpassing SH mode by 5.55 µW cm-2 in the morning. In the afternoon, it generates a Pmax of 18.59 µW cm-2 in SH mode, outperforming RC mode by 15.56 µW cm-2 . This work contributes to the advancement of wearable electronics, offering a sustainable power source in a wearable form.

Hierarchically Superstructured Anisotropic Carbon Particles by Multiscale Assembly Driven by Spinodal Decomposition.

Hierarchical superstructures have novel shape-dependent properties, but well-defined anisotropic carbon superstructures with controllable size, shape, and building block dimensionality have rarely been accomplished thus far. Here, a hierarchical assembly technique is presented that uses spinodal decomposition (SD) to synthesize anisotropic oblate particles of mesoporous carbon superstructure (o-MCS) with nanorod arrays by integrating block-copolymer (BCP) self-assembly and polymer-polymer interface behaviors in binary blends. The interaction of major and minor phases in binary polymer blends leads to the formation of an anisotropic oblate particle, and the BCP-rich phase enables ordered packing and unidirectional alignment of carbon nanorods. Consequently, this approach enables precise control over particles' size, shape, and over the dimensionality of their components. Exploiting this functional superstructure, o-MCS are used as an anode material in potassium-ion batteries, and achieve a notable specific capacity of 156 mA h g-1 at a current density of 2 A g-1, and long-term stability for 3000 cycles. This work presents a significant advancement in the field of hierarchical superstructures, providing a promising strategy for the design and synthesis of anisotropic carbon materials with controlled properties, offering promising applications in energy storage and beyond.

Facilely Modified Nickel-Based Hole Transporting Layers for Organic Solar Cells with 19.12% Efficiency and Enhanced Stability.

Hole transporting layers (HTLs), strategically positioned between electrode and light absorber, play a pivotal role in shaping charge extraction and transport in organic solar cells (OSCs). However, the commonly used poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) HTL, with its hygroscopic and acidic nature, undermines the operational durability of OSC devices. Herein, an environmentally friendly approach is developed utilizing nickel acetate tetrahydrate (NiAc·4H2O) and [2-(9H-carbazol-9-yl)ethyl] phosphonic acid (2PACz) as the NiAc·4H2O/2PACz HTL, aiming at overcoming the limitations posed by the conventional PEDOT:PSS one. Encouragingly, a remarkable power conversion efficiency (PCE) of 19.12% is obtained for the OSCs employing NiAc·4H2O/2PACz as the HTL, surpassing that of devices with the PEDOT:PSS HTL (17.59%), which is ranked among the highest ones of OSCs. This improvement is attributed to the appropriate work function, enhanced hole mobility, facilitated exciton dissociation efficiency, and lower recombination loss of NiAc·4H2O/2PACz-based devices. Furthermore, the NiAc·4H2O/2PACz-based OSCs exhibit superior operational stability compared to their PEDOT:PSS-based counterparts. Of significant note, the NiAc·4H2O/2PACz HTL demonstrates a broad generality, boosting the PCE of the PM6:PY-IT and PM6:Y6-based OSCs from 16.47% and 16.79% (with PEDOT:PSS-based analogs as HTLs) to 17.36% and 17.57%, respectively. These findings underscore the substantial potential of the NiAc·4H2O/2PACz HTL in advancing OSCs, offering improved performance and stability, thereby opening avenue for highly efficient and reliable solar energy harvesting technologies.

Spinodal Decomposition-Driven Structural Hierarchy of Mesoporous Inorganic Materials for Energy Applications.

ConspectusMesoporous inorganic materials (MIMs) directed by block copolymers (BCPs) have attracted tremendous attention due to their high surface area, large pore volume, and tunable pore size. The structural hierarchy of inorganic materials with designed meso- and macrostructures combines the benefits of mesoporosity and tailored macrostructures in which macropores have increased ion/mass transfer and large capacity to carry guest material and have a macroscale particle morphology that permits close packing and a low surface energy. Existing methods for hierarchically structured MIMs require complicated multistep procedures including preparation of sacrificial macrotemplates (e.g., foams and colloidal spheres). Despite considerable efforts to control the macrostructures of mesoporous materials, major challenges remain in the formation of a structural hierarchy with ordered mesoporosity.In polymer science, spinodal decomposition (SD) is a physical phenomenon that spontaneously produces a wide variety of macroscale heterostructures from interconnected networks to isolated droplets. Exploitation of SD is a promising method to achieve precise control of the macrostructure (e.g., macropore, particle morphology) and mesostructure (e.g., pore size and structure, composition) of inorganic materials. However, this approach for tailoring the structural hierarchy of MIMs is unexplored due to the lack of effective systems that can control the complex thermodynamic interactions of inorganic precursor/polymer blends and the phase-separation kinetics.In this Account, we present our recent research progress on the development of synthesis systems that combine unique SD behaviors and BCP self-assembly in polymer blends. To generate macropores in MIMs, we have exploited interconnected macrostructures of SD induced by designed quench conditions of multicomponent blends containing BCP. These strategies enable control of the size of the macropores of the nanostructures independently and can be extended to various compositions (e.g., carbon, SiO2, TiO2, WO3, TiNb2O7, TiN). We also control the macroscopic morphology of the MIMs into spherical particles (e.g., solid and hollow mesoporous spheres) by using SD induced by increasing the mixing entropy penalty of polymer blends that consist BCP, homopolymer(s), and inorganic precursors. Furthermore, interfacial tension between polymers determines the macroscopic morphology of MIMs, from isotropic to anisotropic mesoporous particles (e.g., oblate, bowl, 2D nanosheet). The interfacial states of the homopolymer determine the pore orientation and particle morphology of BCP-directed MIMs.We also highlight the application of the hierarchically structured MIMs in energy storage devices. Generated macropores facilitate ion/mass transfer in lithium-ion batteries and stable accommodation of a large amount of sulfur in lithium-sulfur batteries. Designed morphologies of MIMs are beneficial to achieve high packing density as electrode materials in potassium-ion batteries and thereby achieve high volumetric capacities.Recent advances in SD-driven synthesis for the structural hierarchy of MIMs will inspire how polymer science can be used as a platform for preparing the designed inorganic materials. Additionally, broadening the polymer and composition repertoire will guide in novel frontiers in the design and applications of MIMs in various fields.

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation.

Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue, as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2s are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host.

Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitors.

Mixed-lineage protein kinase 3 (MLK3) is implicated in several human cancers and neurodegenerative diseases. A series of 3H-imidazo[4,5-b]pyridine derivatives were designed, synthesized and evaluated as novel MLK3 inhibitors. A homology model of MLK3 was developed and all designed compounds were docked to assess their binding pattern and affinity toward the MLK3 active site. Based on this knowledge, we synthesized and experimentally evaluated the designed compounds. Majority of the compounds showed significant inhibition of MLK3 in the enzymatic assay. In particular, compounds 9a, 9e, 9j, 9 k, 12b and 12d exhibited IC50 values of 6, 6, 8, 11, 14 and 14 nM, respectively. Furthermore, compounds 9a, 9e, 9 k and 12b exhibited favorable physicochemical properties among these compounds.

Clinical outcomes of transarterial chemoembolization in Child-Turcotte Pugh class A patients with a single small (≤3 cm) hepatocellular carcinoma.

BACKGROUND AND AIM: Transarterial chemoembolization (TACE) is one of the standard modalities used to treat unresectable hepatocellular carcinoma (HCC), but the effectiveness of TACE for treating patients with a solitary small (≤3 cm) HCC and well-preserved liver function has not been definitively established. This study aimed to determine the therapeutic impact of TACE in patients with these characteristics. METHODS: This multicenter (four university hospitals) retrospective cohort study analyzed the medical records of 250 patients with a solitary small (≤3 cm) HCC and Child-Turcotte-Pugh (CTP) class A liver function diagnosed over 10 years. Posttreatment outcomes, including overall survival (OS), recurrence-free survival (RFS), and adverse events, were assessed following TACE therapy. RESULTS: One hundred and thirty-eight of the 250 patients (55.2%) treated with TACE achieved complete remission (CR). Overall median OS was 77.7 months, and median OS was significantly longer in the CR group than in the non-CR group (89.1 vs. 58.8 months, P = 0.001). Median RFS was 19.1 months in the CR group. Subgroup analysis identified hypertension, an elevated serum albumin level, and achieving CR as significant positive predictors of OS, whereas diabetes, hepatitis c virus infection, and tumor size (>2 cm) were poor prognostic factors of OS. CONCLUSIONS: The study demonstrates the effectiveness of TACE as a viable alternative for treating solitary small (≤3 cm) HCC in CTP class A patients.

Pre-Sepsis Length of Hospital Stay and Mortality: A Nationwide Multicenter Cohort Study.

BACKGROUND: Prolonged length of hospital stay (LOS) is associated with an increased risk of hospital-acquired conditions and worse outcomes. We conducted a nationwide, multicenter, retrospective cohort study to determine whether prolonged hospitalization before developing sepsis has a negative impact on its prognosis. METHODS: We analyzed data from 19 tertiary referral or university-affiliated hospitals between September 2019 and December 2020. Adult patients with confirmed sepsis during hospitalization were included. In-hospital mortality was the primary outcome. The patients were divided into two groups according to their LOS before the diagnosis of sepsis: early- (< 5 days) and late-onset groups (≥ 5 days). Conditional multivariable logistic regression for propensity score matched-pair analysis was employed to assess the association between late-onset sepsis and the primary outcome. RESULTS: A total of 1,395 patients were included (median age, 68.0 years; women, 36.3%). The early- and late-onset sepsis groups comprised 668 (47.9%) and 727 (52.1%) patients. Propensity score-matched analysis showed an increased risk of in-hospital mortality in the late-onset group (adjusted odds ratio [aOR], 3.00; 95% confidence interval [CI], 1.69-5.34). The same trend was observed in the entire study population (aOR, 1.85; 95% CI, 1.37-2.50). When patients were divided into LOS quartile groups, an increasing trend of mortality risk was observed in the higher quartiles (P for trend < 0.001). CONCLUSION: Extended LOS before developing sepsis is associated with higher in-hospital mortality. More careful management is required when sepsis occurs in patients hospitalized for ≥ 5 days.

Change in Femoral Cartilage Cross-Sectional Area After Aerobic and Resistance Exercise.

We compared the immediate response and recovery of femoral cartilage morphology following aerobic or resistance exercise to a control condition. Fifteen healthy young males (23.9 years; 170.1 cm; 69.7 kg) visited the laboratory three separate days and randomly performed one of the 30-min exercise aerobic exercises (treadmill running), resistance exercises (leg presses, back squats, and knee extensions), or seated rest as the control, each followed by the 50-min recovery. Ultrasonographic images of the femoral cartilage cross-sectional area (CSA) were obtained before and after exercise and every 5 min thereafter. To test exercise effects over time, a mixed model analysis of variance and Tukey-Kramer post-hoc tests were performed (p<0.05). The femoral cartilage CSA was different (condition×time: F34,742=4.30, p<0.0001) and the femoral cartilage CSA was decreased after the aerobic (-5.8%, p<0.0001) and the resistance (-3.4%, p=0.04) exercises compared to the pre-exercise levels. Deformed femoral cartilage CSA took 35 and 10 min to return to the pre-exercise levels after aerobic and resistance exercises (p+>+0.09), respectively. Thirty minutes of moderate exertion performing aerobic or resistance exercises immediately reduced the femoral cartilage CSA. A rest period ranging from 10 to 35 min was required for cartilage recovery after weight-bearing exercises.

The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease.

Leucine-rich repeat kinase 2 (LRRK2) has been identified by genome-wide association studies as being encoded by a major susceptibility gene for Crohn's disease. Here we found that LRRK2 deficiency conferred enhanced susceptibility to experimental colitis in mice. Mechanistic studies showed that LRRK2 was a potent negative regulator of the transcription factor NFAT and was a component of a complex that included the large noncoding RNA NRON (an NFAT repressor). Furthermore, the risk-associated allele encoding LRRK2 Met2397 identified by a genome-wide association study for Crohn's disease resulted in less LRRK2 protein post-translationally. Severe colitis in LRRK2-deficient mice was associated with enhanced nuclear localization of NFAT1. Thus, our study defines a new step in the control of NFAT activation that involves an immunoregulatory function of LRRK2 and has important implications for inflammatory bowel disease.

LPA1-mediated inhibition of CXCR4 attenuates CXCL12-induced signaling and cell migration.

BACKGROUND: G protein-coupled receptor heteromerization is believed to exert dynamic regulatory impact on signal transduction. CXC chemokine receptor 4 (CXCR4) and its ligand CXCL12, both of which are overexpressed in many cancers, play a pivotal role in metastasis. Likewise, lysophosphatidic acid receptor 1 (LPA1) is implicated in cancer cell proliferation and migration. In our preliminary study, we identified LPA1 as a prospective CXCR4 interactor. In the present study, we investigated in detail the formation of the CXCR4-LPA1 heteromer and characterized the unique molecular features and function of this heteromer. METHODS: We employed bimolecular fluorescence complementation, bioluminescence resonance energy transfer, and proximity ligation assays to demonstrate heteromerization between CXCR4 and LPA1. To elucidate the distinctive molecular characteristics and functional implications of the CXCR4-LPA1 heteromer, we performed various assays, including cAMP, BRET for G protein activation, ß-arrestin recruitment, ligand binding, and transwell migration assays. RESULTS: We observed that CXCR4 forms heteromers with LPA1 in recombinant HEK293A cells and the human breast cancer cell line MDA-MB-231. Coexpression of LPA1 with CXCR4 reduced CXCL12-mediated cAMP inhibition, ERK activation, Gαi/o activation, and ß-arrestin recruitment, while CXCL12 binding to CXCR4 remained unaffected. In contrast, CXCR4 had no impact on LPA1-mediated signaling. The addition of lysophosphatidic acid (LPA) further hindered CXCL12-induced Gαi/o recruitment to CXCR4. LPA or alkyl-OMPT inhibited CXCL12-induced migration in various cancer cells that endogenously express both CXCR4 and LPA1. Conversely, CXCL12-induced calcium signaling and migration were increased in LPAR1 knockout cells, and LPA1-selective antagonists enhanced CXCL12-induced Gαi/o signaling and cell migration in the parental MDA-MB-231 cells but not in LPA1-deficient cells. Ultimately, complete inhibition of cell migration toward CXCL12 and alkyl-OMPT was only achieved in the presence of both CXCR4 and LPA1 antagonists. CONCLUSIONS: The presence and impact of CXCR4-LPA1 heteromers on CXCL12-induced signaling and cell migration have been evidenced across various cell lines. This discovery provides crucial insights into a valuable regulatory mechanism of CXCR4 through heteromerization. Moreover, our findings propose a therapeutic potential in combined CXCR4 and LPA1 inhibitors for cancer and inflammatory diseases associated with these receptors, simultaneously raising concerns about the use of LPA1 antagonists alone for such conditions. Video Abstract.

Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor.

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 µM) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

Immunotherapy for keratinocyte cancers. Part I: Immune-related epidemiology, risk factors, pathogenesis, and immunotherapy management of keratinocyte cancers.

The important role of the immune system in the surveillance and control of keratinocyte cancers (KCs), namely squamous and basal cell carcinomas, is increasingly appreciated, as new immunotherapies have recently become available. As the field of immunotherapy is rapidly evolving, this review synthesizes key concepts and highlights important cellular components within the immune system responsible for attacking KCs. We review the most current data on the epidemiology, risk factors, and immunotherapy management for KCs. Patients will seek advice from dermatologists to help explain why immunotherapies work for KCs and whether they might be appropriate for different clinical scenarios. Collaboration with medical colleagues across different disciplines to evaluate KCs for response to immunotherapy and early recognition of immune-related adverse events will help to optimize patient outcomes.