Linearization of wavelength sweeping lasers for the construction of 4-D FMCW LiDAR images of slow-moving objects using baseband beat note signals.

A FMCW LiDAR system of both the distributed feedback laser and external cavity laser is established in baseband beat notes, rather than up-conversion to an intermediate frequency to exclude flicker noise. Meanwhile, utilizing fast-scanning MEMS mirrors, high-quality real-time (1 fps) 4-D images of the slow-moving object (10 mm/s) can be directly constructed at the baseband with a central frequency as low as 100 kHz and a small Doppler shift. The proposed LiDAR architecture based on such a low-frequency baseband significantly improves the optical power budget on the transmitter side and eliminates the costly high-speed sampling circuits on the receiver side.

Megakaryocytic IGF1 coordinates activation and ferroptosis to safeguard hematopoietic stem cell regeneration after radiation injury.

BACKGROUND: Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood. METHODS: A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice. RESULTS: Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression. CONCLUSIONS: Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.

FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

Blockade of V-domain immunoglobulin suppressor of T-cell activation reprograms tumour-associated macrophages and improves efficacy of PD-1 inhibitor in gastric cancer.

BACKGROUND AND AIMS: In gastric cancer, the response rate of programmed cell death protein-1 (PD-1) inhibitor is far from satisfactory, indicating additional nonredundant pathways might hamper antitumour immunity. V-domain immunoglobulin suppressor of T-cell activation (VISTA) has been reported in several malignancies as a novel immune-checkpoint. Nevertheless, the role of VISTA in gastric cancer still remains obscure. Our purpose is to explore the clinical significance and potential mechanism of VISTA in affecting gastric cancer patients' survival and immunotherapeutic responsiveness. METHODS: Our study recruited eight independent cohorts with a total of 1403 gastric cancer patients. Immunohistochemistry, multiplex immunofluorescence, flow cytometry or intracellular flow cytometry, quantitative polymerase chain reaction, western blotting, fluorescence-activated cell sorting, magnetic-activated cell sorting, smart-seq2, in vitro cell co-culture and ex vivo tumour inhibition assays were applied to investigate the clinical significance and potential mechanism of VISTA in gastric cancer. RESULTS: VISTA was predominantly expressed on tumour-associated macrophages (TAMs), and indicated poor clinical outcomes and inferior immunotherapeutic responsiveness. VISTA+ TAMs showed a mixed phenotype. Co-culture of TAMs and CD8+ T cells indicated that VISTA+ TAMs attenuated effective function of CD8+ T cells. Blockade of VISTA reprogrammed TAMs to a proinflammatory phenotype, reactivated CD8+ T cells and promoted apoptosis of tumour cells. Moreover, blockade of VISTA could also enhance the efficacy of PD-1 inhibitor, suggesting that blockade of VISTA might synergise with PD-1 inhibitor in gastric cancer. CONCLUSIONS: Our data revealed that VISTA was an immune-checkpoint associated with immunotherapeutic resistance. Blockade of VISTA reprogrammed TAMs, promoted T-cell-mediated antitumour immunity, and enhanced efficacy of PD-1 inhibitor, which might have implications in the treatment of gastric cancer.

Subcutaneous fat thickness and abdominal depth are risk factors for surgical site infection after gastric cancer surgery.

BACKGROUND: Surgical site infection (SSI) is one of the most common complications after gastric cancer (GC) surgery. The occurrence of SSI can lead to a prolonged postoperative hospital stay and increased medical expenses, and it can also affect postoperative rehabilitation and the quality of life of patients. Subcutaneous fat thickness (SFT) and abdominal depth (AD) can be used as predictors of SSI in patients undergoing radical resection of GC. AIM: To explore the potential relationship between SFT or AD and SSI in patients undergoing elective radical resection of GC. METHODS: Demographic, clinical, and pre- and intraoperative information of 355 patients who had undergone elective radical resection of GC were retrospectively collected from hospital electronic medical records. Univariate analysis was performed to screen out the significant parameters, which were subsequently analyzed using binary logistic regression and receiver-operating characteristic curve analysis. RESULTS: The prevalence of SSI was 11.27% (40/355). Multivariate analyses revealed that SFT [odds ratio (OR) = 1.150; 95% confidence interval (95%CI): 1.090-1.214; P < 0.001], AD (OR = 1.024; 95%CI: 1.009-1.040; P = 0.002), laparoscopic-assisted surgery (OR = 0.286; 95%CI: 0.030-0.797; P = 0.017), and operation time (OR = 1.008; 95%CI: 1.001-1.015; P = 0.030) were independently associated with the incidence of SSI after elective radical resection of GC. In addition, the product of SFT and AD was a better potential predictor of SSI in these patients than either SFT or AD alone. CONCLUSION: SFT and AD are independent risk factors and can be used as predictors of SSI in patients undergoing radical resection of GC.

Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury.

BACKGROUND: The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. METHODS: A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. RESULTS: In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-ß (IFN-ß) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. CONCLUSIONS: Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-ß-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.

A2AR eGFP reporter mouse enables elucidation of A2AR expression dynamics during anti-tumor immune responses.

There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the A2AR receptor. Understanding of the mechanism by which A2AR is regulated has been hindered by difficulty in identifying the cell types that express A2AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an A2AR eGFP reporter mouse is developed, enabling the expression of A2AR during ongoing anti-tumor immune responses to be assessed. This reveals that A2AR is highly expressed on all tumor-infiltrating lymphocyte subsets including Natural Killer (NK) cells, NKT cells, γδ T cells, conventional CD4+ and CD8+ T lymphocytes and on a MHCIIhiCD86hi subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1+A2AR- cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates A2AR and synergizes with A2AR deficiency to improve anti-tumor immunity. These studies provide insight into the biology of A2AR in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches.

CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity.

CXCL9 expression is a strong predictor of response to immune checkpoint blockade therapy. Accordingly, we sought to develop therapeutic strategies to enhance the expression of CXCL9 and augment antitumor immunity. To perform whole-genome CRISPR-Cas9 screening for regulators of CXCL9 expression, a CXCL9-GFP reporter line is generated using a CRISPR knockin strategy. This approach finds that IRF1 limits CXCL9 expression in both tumor cells and primary myeloid cells through induction of SOCS1, which subsequently limits STAT1 signaling. Thus, we identify a subset of STAT1-dependent genes that do not require IRF1 for their transcription, including CXCL9. Targeting of either IRF1 or SOCS1 potently enhances CXCL9 expression by intratumoral macrophages, which is further enhanced in the context of immune checkpoint blockade therapy. We hence show a non-canonical role for IRF1 in limiting the expression of a subset of STAT1-dependent genes through induction of SOCS1.

Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment.

Although DNA mutation drives stem cell aging, how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood. Here, using a mouse model of irradiation-induced premature aging and middle-aged mice, we show that DNA mutation accumulation in hematopoietic stem cells (HSCs) during aging upregulates their surface expression of major histocompatibility complex class II (MHCII). MHCII upregulation increases the chance for recognition by bone marrow (BM)-resident regulatory T cells (Tregs), resulting in their clonal expansion and accumulation in the HSC niche. On the basis of the establishment of connexin 43 (Cx43)-mediated gap junctions, BM Tregs transfer cyclic adenosine monophosphate (cAMP) to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A (PKA) signaling. Importantly, targeting the HSC-Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs. These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.

Realizing High Brightness Quasi-2D Perovskite Light-Emitting Diodes with Reduced Efficiency Roll-Off via Multifunctional Interface Engineering.

Quasi-2D perovskites have recently flourished in the field of luminescence due to the quantum-confinement effect and the efficient energy transfer between different n phases resulting in exceptional optical properties. However, owing to the lower conductivity and poor charge injection, quasi-2D perovskite light-emitting diodes (PeLEDs) typically suffer from low brightness and high-efficiency roll-off at high current densities compared to 3D perovskite-based PeLEDs, which is undoubtedly one of the most critical issues in this field. In this work, quasi-2D PeLEDs with high brightness, reduced trap density, and low-efficiency roll-off are successfully demonstrated by introducing a thin layer of conductive phosphine oxide at the perovskite/electron transport layer interface. The results surprisingly show that this additional layer does not improve the energy transfer between multiple quasi-2D phases in the perovskite film, but purely improves the electronic properties of the perovskite interface. On the one hand, it passivates the surface defects of the perovskite film; on the other hand, it promotes electron injection and prevents hole leakage across this interface. As a result, the modified quasi-2D pure Cs-based device shows a maximum brightness of > 70,000 cd m-2 (twice that of the control device), a maximum external quantum efficiency (EQE) of > 10% and a much lower efficiency roll-off at high bias voltages.

Creation of Chitosan-Based Nanocapsule-in-Nanofiber Structures for Hydrophobic/Hydrophilic Drug Co-Delivery and Their Dressing Applications in Diabetic Wounds.

Nanofiber meshes (NFMs) loaded with therapeutic agents are very often employed to treat hard-to-heal wounds such as diabetic wounds. However, most of the NFMs have limited capability to load multiple or hydrophilicity distinctive-therapeutic agents. The therapy strategy is therefore significantly hampered. To tackle the innate drawback associated with the drug loading versatility, a chitosan-based nanocapsule-in-nanofiber (NC-in-NF) structural NFM system is developed for simultaneous loading of hydrophobic and hydrophilic drugs. Oleic acid-modified chitosan is first converted into NCs by the developed mini-emulsion interfacial cross-linking procedure, followed by loading a hydrophobic anti-inflammatory agent Curcumin (Cur) into the NCs. Sequentially, the Cur-loaded NCs are successfully introduced into reductant-responsive maleoyl functional chitosan/polyvinyl alcohol NFMs containing a hydrophilic antibiotic Tetracycline hydrochloride. Having a co-loading capability for hydrophilicity distinctive agents, biocompatibility, and a controlled release property, the resulting NFMs have demonstrated the efficacy on promoting wound healing either in normal or diabetic rats.

Should Patients with Renal Cell Carcinoma and Pathological Nodal Invasion Be Classified As Having Stage IV Disease?

BACKGROUND: Lymph node invasion is associated with poor outcome in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with RCC within a single center from 2001 to 2018 were retrospectively obtained from the Chang Gung Research Database. Patient gender, physical status, Charlson Comorbidity Index, tumor side, histology, age at diagnosis, and body mass index (BMI) were compared. The overall survival (OS) and cancer-specific survival (CSS) of each group were estimated using the Kaplan-Meier method. Log-rank tests were used to compare between the subgroups. RESULTS AND CONCLUSIONS: A total of 335 patients were enrolled, of whom 76 had pT3N0M0, 29 had pT1-3N1M0, 104 had T1-4N0M1, and 126 had T1-4N1M1 disease. Significant OS difference was noted between pT3N0M0 and pT1-3N1M0 groups with 12.08 years [95% confidence interval (CI), 8.33-15.84] versus 2.58 years (95% CI, 1.32-3.85), respectively (P < 0.005). No significant difference was observed in OS between pT1-3N1M0 and T1-4N0M1 groups with 2.58 years (95% CI, 1.32-3.85) versus 2.50 years (95% CI, 1.85-3.15, P = 0.72). The OS of N1M1 group was worse than that of N0M1 group with 1.00 year (95% CI, 0.74-1.26) versus 2.50 years (95% CI, 1.85-3.15, P < 0.05). Similar results were also observed in CSS. In summary, we claim that RCC with lymph node (LN) invasion should be reclassified as stage IV disease in terms of survival outcome.

Spatial analysis with SPIAT and spaSim to characterize and simulate tissue microenvironments.

Spatial proteomics technologies have revealed an underappreciated link between the location of cells in tissue microenvironments and the underlying biology and clinical features, but there is significant lag in the development of downstream analysis methods and benchmarking tools. Here we present SPIAT (spatial image analysis of tissues), a spatial-platform agnostic toolkit with a suite of spatial analysis algorithms, and spaSim (spatial simulator), a simulator of tissue spatial data. SPIAT includes multiple colocalization, neighborhood and spatial heterogeneity metrics to characterize the spatial patterns of cells. Ten spatial metrics of SPIAT are benchmarked using simulated data generated with spaSim. We show how SPIAT can uncover cancer immune subtypes correlated with prognosis in cancer and characterize cell dysfunction in diabetes. Our results suggest SPIAT and spaSim as useful tools for quantifying spatial patterns, identifying and validating correlates of clinical outcomes and supporting method development.

Cholesterol confers ferroptosis resistance onto myeloid-biased hematopoietic stem cells and prevents irradiation-induced myelosuppression.

There is growing appreciation that hematopoietic alterations underpin the ubiquitous detrimental effects of metabolic disorders. The susceptibility of bone marrow (BM) hematopoiesis to perturbations of cholesterol metabolism is well documented, while the underlying cellular and molecular mechanisms remain poorly understood. Here we reveal a distinct and heterogeneous cholesterol metabolic signature within BM hematopoietic stem cells (HSCs). We further show that cholesterol directly regulates maintenance and lineage differentiation of long-term HSCs (LT-HSCs), with high levels of intracellular cholesterol favoring maintenance and myeloid bias of LT-HSCs. During irradiation-induced myelosuppression, cholesterol also safeguards LT-HSC maintenance and myeloid regeneration. Mechanistically, we unravel that cholesterol directly and distinctively enhances ferroptosis resistance and boosts myeloid but dampens lymphoid lineage differentiation of LT-HSCs. Molecularly, we identify that SLC38A9-mTOR axis mediates cholesterol sensing and signal transduction to instruct lineage differentiation of LT-HSCs as well as to dictate ferroptosis sensitivity of LT-HSCs through orchestrating SLC7A11/GPX4 expression and ferritinophagy. Consequently, myeloid-biased HSCs are endowed with a survival advantage under both hypercholesterolemia and irradiation conditions. Importantly, a mTOR inhibitor rapamycin and a ferroptosis inducer imidazole ketone erastin prevent excess cholesterol-induced HSC expansion and myeloid bias. These findings unveil an unrecognized fundamental role of cholesterol metabolism in HSC survival and fate decisions with valuable clinical implications.

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non-Small Cell Lung Cancer in a Southeast Asian Country.

Purpose: Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non-small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia. Methods: This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan-Meier method. Results: There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant (P=0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P<0.01). Conclusion: Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.

Stabilization of a high-spin three-coordinate Fe(iii) imidyl complex by radical delocalization.

High-spin, late transition metal imido complexes have attracted significant interest due to their group transfer reactivity and catalytic C-H activation of organic substrates. Reaction of a new two-coordinate iron complex, Fe{N( t Bu)Dipp}2 (1, Dipp = 2,6-diisopropylphenyl), with mesitylazide (MesN3) afforded a three-coordinate Fe-imidyl complex, Fe{N( t Bu)Dipp}2([double bond, length as m-dash]NMes) (2). X-ray crystallographic characterization of single crystals of 2 showed a long Fe-N distance of 1.761(1) Å. Combined magnetic and spectroscopic (Mössbauer and X-ray absorption near edge structure spectroscopy, XANES) characterization of 2 suggests that it has an S = 2 ground state comprising an S = 5/2 Fe(iii) center antiferromagnetically coupled to an S = 1/2 imidyl ligand. Reaction of 1 and 1-azidoadamantane (AdN3) generated a putative, transient Fe{N( t Bu)Dipp}2([double bond, length as m-dash]NAd) (3') complex that yielded an intramolecular C-H amination product, Fe{N( t Bu)Dipp}{κ2-N,N'-_N(CMe2CH2̲NHAd)Dipp} (3). Quantum mechanical calculations further confirmed the spectroscopic assignment of 2 and 3', as well as the differences in their stability and reactivity. Importantly, imidyl radical delocalization onto the mesityl ring significantly increased the stability of 2 and reduced its reactivity toward potential hydrogen atom transfer (HAT) reagents. In contrast, quantum mechanical calculations of 3' revealed that the radical was solely localized on the imidyl N, leading to a high reactivity toward the proximal C-H bond of the N( t Bu)Dipp- ligand.

Phosphate Metabolic Inhibition Contributes to Irradiation-Induced Myelosuppression through Dampening Hematopoietic Stem Cell Survival.

Myelosuppression is a common and intractable side effect of cancer therapies including radiotherapy and chemotherapy, while the underlying mechanism remains incompletely understood. Here, using a mouse model of radiotherapy-induced myelosuppression, we show that inorganic phosphate (Pi) metabolism is acutely inhibited in hematopoietic stem cells (HSCs) during irradiation-induced myelosuppression, and closely correlated with the severity and prognosis of myelosuppression. Mechanistically, the acute Pi metabolic inhibition in HSCs results from extrinsic Pi loss in the bone marrow niche and the intrinsic transcriptional suppression of soluble carrier family 20 member 1 (SLC20A1)-mediated Pi uptake by p53. Meanwhile, Pi metabolic inhibition blunts irradiation-induced Akt hyperactivation in HSCs, thereby weakening its ability to counteract p53-mediated Pi metabolic inhibition and the apoptosis of HSCs and consequently contributing to myelosuppression progression. Conversely, the modulation of the Pi metabolism in HSCs via a high Pi diet or renal Klotho deficiency protects against irradiation-induced myelosuppression. These findings reveal that Pi metabolism and HSC survival are causally linked by the Akt/p53-SLC20A1 axis during myelosuppression and provide valuable insights into the pathogenesis and management of myelosuppression.

Total Synthesis of Resiniferatoxin.

From both structural and functional perspectives, the large family of daphnane diterpene orthoesters (DDOs) represent a truly remarkable class of natural products. As potent lead compounds for the treatment of pain, neurodegeneration, HIV/AIDS, and cancer, their medicinal potential continues to be heavily investigated, yet synthetic routes to DDO natural products remain rare. Herein we report a distinct approach to this class of complex diterpenes, highlighted by a 15-step total synthesis of the flagship DDO, resiniferatoxin.