TERT activation targets DNA methylation and multiple aging hallmarks.

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

Histone demethylase KDM5D upregulation drives sex differences in colon cancer.

Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP)2, revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.

Opposing roles of TGFß and BMP signaling in prostate cancer development.

SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor ß (TGFß) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFß receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFß-BMP signaling and illuminate potential therapeutic targets for prostate cancer.

A Non-π-Conjugated Molecular Crystal with Balanced Second-Harmonic Generation, Bandgap, and Birefringence.

Traditional nonlinear optical (NLO) crystals are exclusively limited to ionic crystals with π-conjugated groups and it is a great challenge to achieve a subtle balance between second-harmonic generation, bandgap, and birefringence for them, especially in the deep-UV spectrum region (Eg  > 6.20 eV). Herein, a non-π-conjugated molecular crystal, NH3 BH3 , which realizes such balance with a large second-harmonic generation response (2.0 × KH2 PO4 at 1064 nm, and 0.45 × ß-BaB2 O4 at 532 nm), deep-UV transparency (Eg > 6.53 eV), and moderate birefringence (Δn = 0.056@550 nm) is reported. As a result, NH3 BH3 exhibits a large quality factor of 0.32, which is evidently larger than those of non-π-conjugated sulfate and phosphate ionic crystals. Using an unpolished NH3 BH3 crystal, effective second-harmonic generation outputs are observed at different wavelengths. These attributes indicate that NH3 BH3 is a promising candidate for deep-UV NLO applications. This work opens up a new door for developing high-performance deep-UV NLO crystals.

AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase.

Prostate cancer is a leading cause of cancer-related mortality in men. The widespread use of androgen receptor (AR) inhibitors has generated an increased incidence of AR-negative prostate cancer, triggering the need for effective therapies for such patients. Here, analysis of public genome-wide CRISPR screens in human prostate cancer cell lines identified histone demethylase JMJD1C (KDM3C) as an AR-negative context-specific vulnerability. Secondary validation studies in multiple cell lines and organoids, including isogenic models, confirmed that small hairpin RNA (shRNA)-mediated depletion of JMJD1C potently inhibited growth specifically in AR-negative prostate cancer cells. To explore the cooperative interactions of AR and JMJD1C, we performed comparative transcriptomics of 1) isogenic AR-positive versus AR-negative prostate cancer cells, 2) AR-positive versus AR-negative prostate cancer tumors, and 3) isogenic JMJD1C-expressing versus JMJD1C-depleted AR-negative prostate cancer cells. Loss of AR or JMJD1C generates a modest tumor necrosis factor alpha (TNFα) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNFα signature in human prostate cancer, suggesting TNFα signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNFα treatment and, conversely, TNFα pathway inhibition via inhibition of its downstream effector MAP4K4 partially reversed the growth defect of JMJD1C-depleted AR-negative prostate cancer cells. Given the deleterious systemic side effects of TNFα therapy in humans and the viability of JMJD1C-knockout mice, the identification of JMJD1C inhibition as a specific vulnerability in AR-negative prostate cancer may provide an alternative drug target for prostate cancer patients progressing on AR inhibitor therapy.

Lanthanide-Doped KMgF3 Upconversion Nanoparticles for Photon Avalanche Luminescence with Giant Nonlinearities.

Lanthanide (Ln3+)-doped photon avalanche (PA) upconversion nanoparticles (UCNPs) have great prospects in many advanced technologies; however, realizing efficient PA luminescence in Ln3+-doped UCNPs remains challenging due to the deleterious surface and lattice quenching effect. Herein, we report a unique strategy based on the pyrolysis of KHF2 for the controlled synthesis of aliovalent Ln3+-doped KMgF3 UCNPs, which can effectively protect Ln3+ from luminescence quenching by surface and internal OH- defects and thereby boost upconversion luminescence. This enables us to realize efficient PA luminescence from Tm3+ at 802 nm in KMgF3: Tm3+ UCNPs upon 1064 nm excitation, with a giant nonlinearity of ∼27, a PA response time of 281 ms, and an excitation threshold of 16.6 kW cm-2. This work may open up a new avenue for exploring highly nonlinear PA luminescence through aliovalent Ln3+ doping and crystal lattice engineering toward diverse emerging applications.

Effective combinatorial immunotherapy for castration-resistant prostate cancer.

A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b+Gr1+) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.

Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer.

Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3ß-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the ß-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF-NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of 'trackable' targets in cancers that harbour specific tumour-suppressor deficiencies.

Enhancing Dye-Triplet-Sensitized Upconversion Emission Through the Heavy-Atom Effect in CsLu2 F7 :Yb/Er Nanoprobes.

Lanthanide (Ln3+ )-doped upconversion (UC) nanoprobes, which have drawn extensive attention for various bioapplications, usually suffer from small absorption cross-sections and weak luminescence intensity of Ln3+ ions. Herein, we report the controlled synthesis of a new class of Ln3+ -doped UC nanoprobes based on CsLu2 F7 :Yb/Er nanocrystals (NCs), which can effectively increase the intersystem crossing (ISC) efficiency from singlet excited state to triplet excited state of IR808 up to 99.3 % through the heavy atom effect. By virtue of the efficient triplet sensitization of IR808, the optimal UC luminescence (UCL) intensity of IR808-modified CsLu2 F7 :Yb/Er NCs is enhanced by 1309 times upon excitation at 808 nm. Benefiting from the intense dye-triplet-sensitized UCL, the nanoprobes are demonstrated for sensitive assay of extracellular and intracellular hypochlorite with an 808-nm/980-nm dual excited ratiometric strategy.

Realization of vis-NIR Dual-Modal Circularly Polarized Light Detection in Chiral Perovskite Bulk Crystals.

Circularly polarized light (CPL)-sensitive direct detection is attracting increasing attention owing to its various optical technology applications and ultracompact device structures. However, current CPL-sensitive direct detection mainly focuses on a single mode, whereas the visible-near-infrared (vis-NIR) dual-modal detection, which is important for improving device sensitivity and night-vision performance, still remains to be explored. Here, for the first time, the vis-NIR dual-modal CPL-sensitive direct detection is presented in bulk single crystals of two-dimensional chiral perovskite (R-BPEA)2PbI4 (R-BPEA = (R)-1-(4-bromophenyl)ethylammonium). Benefiting from the strong light-matter interaction of the layered structure, (R-BPEA)2PbI4 shows a two-photon absorption (TPA) coefficient of up to 55 cm/MW, which almost falls around the highest value of 2D hybrid perovskites. Notably, (R-BPEA)2PbI4 exhibits a high vis-NIR dual-modal CPL-sensitive direct detecting performance under both visible light (520 nm) and NIR light (800 nm), with the on/off ratios of current higher than 103, and the anisotropy factors for photocurrent higher than 0.1. This work will shed light on the design of new chiral semiconductors with a large TPA coefficient and promote their applications in vis-NIR dual-modal CPL-sensitive direct detection.

Virtual Reality Rehabilitation Versus Conventional Physical Therapy for Improving Balance and Gait in Parkinson's Disease Patients: A Randomized Controlled Trial.

BACKGROUND The aim of this study was to investigate the effect of virtual reality (VR) technology on balance and gait in patients with Parkinson's disease (PD). MATERIAL AND METHODS The study design was a single-blinded, randomized, controlled study. Twenty-eight patients with PD were randomly divided into the experimental group (n=14) and the control group (n=14). The experimental group received VR training, and the control group received conventional physical therapy. Patients performed 45 minutes per session, 5 days a week, for 12 weeks. Individuals were assessed pre- and post-rehabilitation with the Berg Balance Scale (BBS), Timed Up and Go Test (TUGT), Third Part of Unified Parkinson's Disease Rating Scale (UPDRS3), and Functional Gait Assessment (FGA). RESULTS After treatment, BBS, TUGT, and FGA scores had improved significantly in both groups (P<0.05). However, there was no significant difference in the UPDRS3 between the pre- and post-rehabilitation data of the control group (P>0.05). VR training resulted in significantly better performance compared with the conventional physical therapy group (P<0.05). CONCLUSIONS The results of this study indicate that 12 weeks of VR rehabilitation resulted in a greater improvement in the balance and gait of individuals with PD when compared to conventional physical therapy.

Graphene-Oxide-Modified Lanthanide Nanoprobes for Tumor-Targeted Visible/NIR-II Luminescence Imaging.

The synthesis of hydrophilic lanthanide-doped nanocrystals (Ln3+ -NCs) with molecular recognition ability for bioimaging currently remains a challenge. Herein, we present an effective strategy to circumvent this bottleneck by encapsulating Ln3+ -NCs in graphene oxide (NCs@GO). Monodisperse NCs@GO was prepared by optimizing GO size and core-shell structure of NaYF4 :Yb,Er@NaYF4 , thus combining the intense visible/near-infrared II (NIR-II) luminescence of NCs and the unique surface properties and biomedical functions of GO. Such nanostructures not only feature broad solvent dispersibility, efficient cell uptake, and excellent biocompatibility but also enable further modifications with various agents such as DNA, proteins, or nanoparticles without tedious procedures. Moreover, we demonstrate in proof-of-concept experiments that NCs@GO can realize simultaneous intracellular tracking and microRNA-21 visualization, as well as highly sensitive in vivo tumor-targeted NIR-II imaging at 1525 nm.

Bilayered Hybrid Perovskite Ferroelectric with Giant Two-Photon Absorption.

Perovskite ferroelectrics with prominent nonlinear optical absorption have attracted great attention in the field of photonics. However, they are traditionally dominated by inorganic oxides and exhibit relatively small nonlinear optical absorption coefficients, which hinder their further applications. Herein, we report a new organic-inorganic hybrid bilayered perovskite ferroelectric, (C4H9NH3)2(NH2CHNH2)Pb2Br7 (1), showing an above-room-temperature Curie temperature (∼322 K) and notable spontaneous polarization (∼3.8 µC cm-2). Significantly, the unique quantum-well structure of 1 results in intriguing two-photon absorption properties with a giant nonlinear optical absorption coefficient as high as 5.76 × 103 cm GW-1, which is almost two-orders of magnitude larger than those of mostly traditional all-inorganic perovskite ferroelectrics. To our best knowledge, 1 is the first example of hybrid ferroelectrics with giant two-photon absorption coefficient. The mechanisms for ferroelectric and two-photon absorption are revealed. This work will shed light on the design of new ferroelectrics with two-photon absorption and promote their potentials in the photonic application.

Mechanisms of the blue emission of NaYF4:Tm(3+) nanoparticles excited by an 800 nm continuous wave laser.

A thorough understanding of energy transfer and upconversion (UC) processes between trivalent lanthanide (Ln(3+)) ions is essential and important for improving UC performance. However, because of the abundant energy states of Ln(3+) ions, UC mechanisms are very complicated, which makes it a challenge to exclusively verify and quantitatively evaluate the dominant process. In this study, the fundamental excitation processes of Tm(3+)-doped NaYF4 nanocrystals under 800 nm continuous wave (CW) laser excitation were experimentally investigated on the basis of the quantum transition principle. An 800 nm CW laser combined with other wavelength CW lasers, including 471 nm, 657 nm, 980 nm, and 1550 nm lasers, were designed to study in-depth the excitation processes of UC luminescence via simultaneous two-wavelength laser excitation. The results indicate that the excited state absorption of (3)H6→(3)H4∼∼(3)H5→(1)G4 is the dominant pathway of the 481 nm and 651 nm emission bands, and two kinds of energy transfer UC pathways, uniformly expressed as (1)G4 + (3)H4→(1)D2 + (3)F4, play the primary roles in the 456 nm emission band.

Upconversion luminescence mechanisms of Er(3+) ions under excitation of an 800 nm laser.

The fundamental processes of upconversion (UC) emissions from trivalent lanthanide ions are essential for designing and improving the performance of UC materials. However, UC mechanisms involve multiple processes in one system because of the abundant energy states, which make it a challenge to exclusively verify and quantitatively evaluate the dominant process. In this paper, the mechanisms of green and red emissions in Er(3+) doped NaYF4-glass ceramics under 800 nm continuous wave laser excitation are studied via excitation power-dependence, polarization-dependence, and the transient evolution. These UC emission properties are compared with those under single-/two-wavelength excitation in a pump-probe system of 800 nm and 1500 nm femtosecond lasers. These results indicate that the excited state absorption pathway of (4)I15/2 → (4)I9/2 → (4)I13/2 → (2)H11/2/(4)S3/2 plays the dominant role in the emission of the green band, and the cross relaxation pathway of (4)I11/2 + (4)I13/2 → (4)F9/2 + (4)I15/2 plays the main role in the emission of the red band.

Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3ß inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.

Toward Efficient Two-Photon Circularly Polarized Light Detection through Cooperative Strategies in Chiral Quasi-2D Perovskites.

Organic-inorganic hybrid perovskites carry unique semiconducting properties and advanced flexible crystal structures. These characteristics of organic-inorganic hybrid perovskites create a promising candidacy for circularly polarized light (CPL) detection. However, CPL detections based on chiral perovskites are limited to UV and visible wavelengths. The natural quantum well structures of layered hybrid perovskites generate strong light-matter interactions. This makes it possible to achieve near-infrared (NIR) CPL detection via two-photon absorption in the sub-wavelength region. In this study, cooperative strategies of dimension increase and mixed spacer cations are used to obtain a pair of chiral multilayered perovskites (R-ß-MPA)EA2 Pb2 Br7 and (S-ß-MPA)EA2 Pb2 Br7 (MPA = methylphenethylammonium and EA = ethylammonium). The distinctive bi-cations interlayer and multilayered inorganic skeletons provide enhanced photoconduction. Moreover, superior photoconduction leads to the prominent NIR CPL response with a responsivity up to 8.1 × 10-5 A W-1 . It is anticipated that this work can serve as a benchmark for the fabrication and optimization of efficient NIR CPL detection by simple chemical design.

AIEgen-sensitized lanthanide nanocrystals as luminescent probes for intracellular Fe3+ monitoring.

The abnormal Fe3+ level is known to cause various diseases, such as heart failure, liver damage and neurodegeneration. In situ probing Fe3+ in living cells or organisms is highly desired for both biological research and medical diagnostics. Herein, hybrid nanocomposites NaEuF4@TCPP were constructed by the assembly of an aggregation-induced emission luminogen (AIEgen) TCPP and NaEuF4 nanocrystals (NCs). The anchored TCPP on the surface of NaEuF4 NCs can reduce rotational relaxation of the excited state and efficiently transfer the energy to the Eu3+ ions with minimized nonradiative energy loss. Consequently, the prepared NaEuF4@TCPP nanoparticles (NPs) exhibited an intense red emission with a 103-fold enhancement relative to that in NaEuF4 NCs under 365 nm excitation. A selectively quenching response to Fe3+ ions for the NaEuF4@TCPP NPs makes them luminescent probes for sensitive detection of Fe3+ ions with a low detection limit of 340 nM. Moreover, the luminescence of NaEuF4@TCPP NPs could be recovered by the addition of iron chelators. Benefiting from their good biocompatibility and stability in living cells, together with the characteristic of the reversible luminescence response, the lipo-coated NaEuF4@TCPP probes were successfully applied for real-time monitoring of Fe3+ ions in living HeLa cells. These results are expected to motivate the exploration of AIE-based lanthanide probes for sensing and biomedical applications.

Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression.

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human colorectal cancer, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven colorectal cancer. SIGNIFICANCE: This study identified a molecular mechanism contributing to KRAS*-driven colorectal cancer progression via fibroblast transformation in the tumor microenvironment to produce VEGFA driving tumor angiogenesis. In preclinical models, targeting the KRAS*-TFCP2-VEGFA axis impaired tumor progression, revealing a potential novel therapeutic option for patients with KRAS*-driven colorectal cancer. This article is featured in Selected Articles from This Issue, p. 2489.