Deformable motion compensation in interventional cone-beam CT with a context-aware learned autofocus metric.

PURPOSE: Interventional Cone-Beam CT (CBCT) offers 3D visualization of soft-tissue and vascular anatomy, enabling 3D guidance of abdominal interventions. However, its long acquisition time makes CBCT susceptible to patient motion. Image-based autofocus offers a suitable platform for compensation of deformable motion in CBCT, but it relies on handcrafted motion metrics based on first-order image properties and that lack awareness of the underlying anatomy. This work proposes a data-driven approach to motion quantification via a learned, context-aware, deformable metric, VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ , that quantifies the amount of motion degradation as well as the realism of the structural anatomical content in the image. METHODS: The proposed VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ was modeled as a deep convolutional neural network (CNN) trained to recreate a reference-based structural similarity metric-visual information fidelity (VIF). The deep CNN acted on motion-corrupted images, providing an estimation of the spatial VIF map that would be obtained against a motion-free reference, capturing motion distortion, and anatomic plausibility. The deep CNN featured a multi-branch architecture with a high-resolution branch for estimation of voxel-wise VIF on a small volume of interest. A second contextual, low-resolution branch provided features associated to anatomical context for disentanglement of motion effects and anatomical appearance. The deep CNN was trained on paired motion-free and motion-corrupted data obtained with a high-fidelity forward projection model for a protocol involving 120 kV and 9.90 mGy. The performance of VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ was evaluated via metrics of correlation with ground truth VIF ${\bm{VIF}}$ and with the underlying deformable motion field in simulated data with deformable motion fields with amplitude ranging from 5 to 20 mm and frequency from 2.4 up to 4 cycles/scan. Robustness to variation in tissue contrast and noise levels was assessed in simulation studies with varying beam energy (90-120 kV) and dose (1.19-39.59 mGy). Further validation was obtained on experimental studies with a deformable phantom. Final validation was obtained via integration of VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ on an autofocus compensation framework, applied to motion compensation on experimental datasets and evaluated via metric of spatial resolution on soft-tissue boundaries and sharpness of contrast-enhanced vascularity. RESULTS: The magnitude and spatial map of VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ showed consistent and high correlation levels with the ground truth in both simulation and real data, yielding average normalized cross correlation (NCC) values of 0.95 and 0.88, respectively. Similarly, VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ achieved good correlation values with the underlying motion field, with average NCC of 0.90. In experimental phantom studies, VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ properly reflects the change in motion amplitudes and frequencies: voxel-wise averaging of the local VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ across the full reconstructed volume yielded an average value of 0.69 for the case with mild motion (2 mm, 12 cycles/scan) and 0.29 for the case with severe motion (12 mm, 6 cycles/scan). Autofocus motion compensation using VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ resulted in noticeable mitigation of motion artifacts and improved spatial resolution of soft tissue and high-contrast structures, resulting in reduction of edge spread function width of 8.78% and 9.20%, respectively. Motion compensation also increased the conspicuity of contrast-enhanced vascularity, reflected in an increase of 9.64% in vessel sharpness. CONCLUSION: The proposed VI F D L ${\bm{VI}}{{\bm{F}}}_{DL}$ , featuring a novel context-aware architecture, demonstrated its capacity as a reference-free surrogate of structural similarity to quantify motion-induced degradation of image quality and anatomical plausibility of image content. The validation studies showed robust performance across motion patterns, x-ray techniques, and anatomical instances. The proposed anatomy- and context-aware metric poses a powerful alternative to conventional motion estimation metrics, and a step forward for application of deep autofocus motion compensation for guidance in clinical interventional procedures.

Highly Invasive Biliary Cancer Presenting as Multiple Extrabiliary Lesions Masquerading as Abscesses.

Carcinosarcomas of the biliary tract are an extremely rare type of malignancy and may be low on a differential when presenting as multiple metastatic masses. In this case report, we report a case of a female who presented with an aggressive late-stage disease whose initial workup did not indicate a malignant process. Further complicating her care, biopsy samples taken from extra-hepatic masses were culture-positive for Lactobacillus rhamnosu. Given the late stage of the patient's disease, hospice care was initiated. The patient passed away four months after the initial presentation.

Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma. SIGNIFICANCE: BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

Deformable Motion Compensation for Intraprocedural Vascular Cone-beam CT with Sequential Projection Domain Targeting and Vessel-Enhancing Autofocus.

Purpose: Cone-beam CT (CBCT) is used in interventional radiology (IR) for identification of complex vascular anatomy, difficult to visualize in 2D fluoroscopy. However, long acquisition time makes CBCT susceptible to soft-tissue deformable motion that degrades visibility of fine vessels. We propose a targeted framework to compensate for deformable intra-scan motion via learned full-sequence models for identification of vascular anatomy coupled to an autofocus function specifically tailored to vascular imaging. Methods: The vessel-targeted autofocus acts in two stages: (i) identification of vascular and catheter targets in the projection domain; and, (ii) autofocus optimization for a 4D vector field through an objective function that quantifies vascular visibility. Target identification is based on a deep learning model that operates on the complete sequence of projections, via a transformer encoder-decoder architecture that uses spatial-temporal self-attention modules to infer long-range feature correlations, enabling identification of vascular anatomy with highly variable conspicuity. The vascular autofocus function is derived through eigenvalues of the local image Hessian, which quantify the local image structure for identification of bright tubular structures. Motion compensation was achieved via spatial transformer operators that impart time dependent deformations to NPAR = 90 partial angle reconstructions, allowing for efficient minimization via gradient backpropagation. The framework was trained and evaluated in synthetic abdominal CBCTs obtained from liver MDCT volumes and including realistic models of contrast-enhanced vascularity with 15 to 30 end branches, 1 - 3.5 mm vessel diameter, and 1400 HU contrast. Results: The targeted autofocus resulted in qualitative and quantitative improvement in vascular visibility in both simulated and clinical intra-procedural CBCT. The transformer-based target identification module resulted in superior detection of target vascularity and a lower number of false positives, compared to a baseline U-Net model acting on individual projection views, reflected as a 1.97x improvement in intersection-over-union values. Motion compensation in simulated data yielded improved conspicuity of vascular anatomy, and reduced streak artifacts and blurring around vessels, as well as recovery of shape distortion. These improvements amounted to an average 147% improvement in cross correlation computed against the motion-free ground truth, relative to the un-compensated reconstruction. Conclusion: Targeted autofocus yielded improved visibility of vascular anatomy in abdominal CBCT, providing better potential for intra-procedural tracking of fine vascular anatomy in 3D images. The proposed method poses an efficient solution to motion compensation in task-specific imaging, with future application to a wider range of imaging scenarios.

Cadmium reduces growth of male fetuses by impairing development of the placental vasculature and reducing expression of nutrient transporters.

In utero exposure to the toxic metal cadmium (Cd) alters fetoplacental growth in rodents and has been inversely associated with birth weight and infant size in some birth cohorts. Moreover, studies suggest that Cd may have differential effects on growth and development according to offspring sex. The purpose of the current study was to evaluate changes in male and female fetoplacental development following a single injection of saline (5 ml/kg ip) or cadmium chloride (CdCl2, 2.5, 5 mg/kg, ip) on gestational day (GD) 9. By GD18, no changes in fetal or placental weights were observed after treatment with 2.5 mg/kg CdCl2. By comparison, the weight and length of male fetuses and their placentas were reduced following treatment with 5 mg/kg CdCl2 whereas no change was observed in females. In addition, the area of maternal and fetal blood vessels as well as the expression of the glucose transporters, Glut1 and Glut3, and the endothelial marker, CD34, were reduced in the placentas of CdCl2-treated male offspring compared to females. Interestingly, the placentas of females accumulated 80% more Cd than males after CdCl2 (5 mg/kg) administration. Female placentas also had higher concentrations of zinc and the zinc transporter Znt1 compared to males which may explain the limited changes in fetal growth observed following CdCl2 treatment. Taken together, disruption of vasculature development and reduced expression of glucose transporters in the placenta provide potential mechanisms underlying reduced fetal growth in male offspring despite the greater accumulation of Cd in female placentas.

A Self-Configuring Deep Learning Network for Segmentation of Temporal Bone Anatomy in Cone-Beam CT Imaging.

OBJECTIVE: Preoperative planning for otologic or neurotologic procedures often requires manual segmentation of relevant structures, which can be tedious and time-consuming. Automated methods for segmenting multiple geometrically complex structures can not only streamline preoperative planning but also augment minimally invasive and/or robot-assisted procedures in this space. This study evaluates a state-of-the-art deep learning pipeline for semantic segmentation of temporal bone anatomy. STUDY DESIGN: A descriptive study of a segmentation network. SETTING: Academic institution. METHODS: A total of 15 high-resolution cone-beam temporal bone computed tomography (CT) data sets were included in this study. All images were co-registered, with relevant anatomical structures (eg, ossicles, inner ear, facial nerve, chorda tympani, bony labyrinth) manually segmented. Predicted segmentations from no new U-Net (nnU-Net), an open-source 3-dimensional semantic segmentation neural network, were compared against ground-truth segmentations using modified Hausdorff distances (mHD) and Dice scores. RESULTS: Fivefold cross-validation with nnU-Net between predicted and ground-truth labels were as follows: malleus (mHD: 0.044 ± 0.024 mm, dice: 0.914 ± 0.035), incus (mHD: 0.051 ± 0.027 mm, dice: 0.916 ± 0.034), stapes (mHD: 0.147 ± 0.113 mm, dice: 0.560 ± 0.106), bony labyrinth (mHD: 0.038 ± 0.031 mm, dice: 0.952 ± 0.017), and facial nerve (mHD: 0.139 ± 0.072 mm, dice: 0.862 ± 0.039). Comparison against atlas-based segmentation propagation showed significantly higher Dice scores for all structures (p < .05). CONCLUSION: Using an open-source deep learning pipeline, we demonstrate consistently submillimeter accuracy for semantic CT segmentation of temporal bone anatomy compared to hand-segmented labels. This pipeline has the potential to greatly improve preoperative planning workflows for a variety of otologic and neurotologic procedures and augment existing image guidance and robot-assisted systems for the temporal bone.

Acute limb ischemia secondary to external iliac and common femoral artery dissection in a body builder.

Spontaneous external iliac artery dissection in highly trained athletes is becoming more recognized, but the reason as to why they are occurring remains a mystery. We present a patient with acute limb ischemia secondary to arterial dissection after strenuous exercise. Imaging showed complete occlusion of the distal common iliac artery, and the patient underwent successful revascularization of the right lower extremity using a hybrid approach.

Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products.

BACKGROUND: Clinical CAR T-cell therapy using integrating vector systems represents a promising approach for the treatment of hematological malignancies. Lentiviral and γ-retroviral vectors are the most commonly used vectors in the manufacturing process. However, the integration pattern of these viral vectors and subsequent effect on CAR T-cell products is still unclear. METHODS: We used a modified viral integration sites analysis (VISA) pipeline to evaluate viral integration events around the whole genome in pre-infusion CAR T-cell products. We compared the differences of integration pattern between lentiviral and γ-retroviral products. We also explored whether the integration sites correlated with clinical outcomes. RESULTS: We found that γ-retroviral vectors were more likely to insert than lentiviral vectors into promoter, untranslated, and exon regions, while lentiviral vector integration sites were more likely to occur in intron and intergenic regions. Some integration events affected gene expression at the transcriptional and post-transcriptional level. Moreover, γ-retroviral vectors showed a stronger impact on the host transcriptome. Analysis of individuals with different clinical outcomes revealed genes with differential enrichment of integration events. These genes may affect biological functions by interrupting amino acid sequences and generating abnormal proteins, instead of by affecting mRNA expression. These results suggest that vector integration is associated with CAR T-cell efficacy and clinical responses. CONCLUSION: We found differences in integration patterns, insertion hotspots and effects on gene expression vary between lentiviral and γ-retroviral vectors used in CAR T-cell products and established a foundation upon which we can conduct further analyses.

Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors.

PURPOSE: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. EXPERIMENTAL DESIGN: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. RESULTS: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti-programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69-CD44+CD62L- T cells, reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. CONCLUSIONS: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010.

Acute mitral valve regurgitation secondary to papillary muscle rupture due to infective endocarditis.

BACKGROUND: Papillary muscle rupture due to infective endocarditis is a rare event and proper management of this condition has not been described in the literature. Our case aims to shed light on treatment strategies for these patients using the current guidelines. CASE PRESENTATION: This case presents a 58-year-old male with acute heart failure secondary to papillary muscle rupture. He underwent an en bloc resection of his mitral valve with a bioprosthetic valve replacement. Specimen pathology later showed necrotic papillary muscle due to infective endocarditis. The patient was further treated with antibiotic therapy. He recovered well post-operatively and continued to do well after discharge. CONCLUSION: In patients who present with papillary muscle rupture secondary to infective endocarditis, clinical symptoms should drive the treatment strategy. Despite the etiology, early mitral valve surgery remains treatment of choice for patients who have papillary muscle rupture leading to acute heart failure. Culture-guided prolonged antibiotic treatment is vital in this category of patients, especially those who have a prosthetic valve implanted.

A cAMP Sensor Based on Ligand-Dependent Protein Stabilization.

cAMP is a ubiquitous second messenger with many functions in diverse organisms. Current cAMP sensors, including Föster resonance energy transfer (FRET)-based and single-wavelength-based sensors, allow for real time visualization of this small molecule in cultured cells and in some cases in vivo. Nonetheless the observation of cAMP in living animals is still difficult, typically requiring specialized microscopes and ex vivo tissue processing. Here we used ligand-dependent protein stabilization to create a new cAMP sensor. This sensor allows specific and sensitive detection of cAMP in living zebrafish embryos, which may enable new understanding of the functions of cAMP in living vertebrates.

Statistical Shape Model of the Temporal Bone Using Segmentation Propagation.

HYPOTHESIS: Automated image registration techniques can successfully determine anatomical variation in human temporal bones with statistical shape modeling. BACKGROUND: There is a lack of knowledge about inter-patient anatomical variation in the temporal bone. Statistical shape models (SSMs) provide a powerful method for quantifying variation of anatomical structures in medical images but are time-intensive to manually develop. This study presents SSMs of temporal bone anatomy using automated image-registration techniques. METHODS: Fifty-three cone-beam temporal bone CTs were included for SSM generation. The malleus, incus, stapes, bony labyrinth, and facial nerve were automatically segmented using 3D Slicer and a template-based segmentation propagation technique. Segmentations were then used to construct SSMs using MATLAB. The first three principal components of each SSM were analyzed to describe shape variation. RESULTS: Principal component analysis of middle and inner ear structures revealed novel modes of anatomical variation. The first three principal components for the malleus represented variability in manubrium length (mean: 4.47 mm; ±2-SDs: 4.03-5.03 mm) and rotation about its long axis (±2-SDs: -1.6° to 1.8° posteriorly). The facial nerve exhibits variability in first and second genu angles. The bony labyrinth varies in the angle between the posterior and superior canals (mean: 88.9°; ±2-SDs: 83.7°-95.7°) and cochlear orientation (±2-SDs: -4.0° to 3.0° anterolaterally). CONCLUSIONS: SSMs of temporal bone anatomy can inform surgeons on clinically relevant inter-patient variability. Anatomical variation elucidated by these models can provide novel insight into function and pathophysiology. These models also allow further investigation of anatomical variation based on age, BMI, sex, and geographical location.

Diffuse Cerebral Edema and Impending Herniation Complicating Hepatic Encephalopathy in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disease characterized by the formation of cutaneous and visceral telangiectasias and arteriovenous malformations (AVM). Multiple organs may be affected, including the nasal mucosa, skin, lungs, gastrointestinal tract, and brain. The following case highlights a unique manifestation of HHT in a patient with a gastrointestinal hemorrhage and epistaxis, resulting in hyperammonemia and diffuse cerebral edema and herniation. Clinicians should be aware of this potential complication in such patients and initiate ammonia-reducing agents early to avoid this devastating consequence.

Automated Extraction of Anatomical Measurements From Temporal Bone CT Imaging.

OBJECTIVE: Proposed methods of minimally invasive and robot-assisted procedures within the temporal bone require measurements of surgically relevant distances and angles, which often require time-consuming manual segmentation of preoperative imaging. This study aims to describe an automatic segmentation and measurement extraction pipeline of temporal bone cone-beam computed tomography (CT) scans. STUDY DESIGN: Descriptive study of temporal bone measurements. SETTING: Academic institution. METHODS: A propagation template composed of 16 temporal bone CT scans was formed with relevant anatomical structures and landmarks manually segmented. Next, 52 temporal bone CT scans were autonomously segmented using deformable registration techniques from the Advanced Normalization Tools Python package. Anatomical measurements were extracted via in-house Python algorithms. Extracted measurements were compared to ground truth values from manual segmentations. RESULTS: Paired t test analyses showed no statistical difference between measurements using this pipeline and ground truth measurements from manually segmented images. Mean (SD) malleus manubrium length was 4.39 (0.34) mm. Mean (SD) incus short and long processes were 2.91 (0.18) mm and 3.53 (0.38) mm, respectively. The mean (SD) maximal diameter of the incus long process was 0.74 (0.17) mm. The first and second facial nerve genus had mean (SD) angles of 68.6 (6.7) degrees and 111.1 (5.3) degrees, respectively. The facial recess had a mean (SD) span of 3.21 (0.46) mm. Mean (SD) minimum distance between the external auditory canal and tegmen was 3.79 (1.05) mm. CONCLUSIONS: This is the first study to automatically extract relevant temporal bone anatomical measurements from CT scans using segmentation propagation. Measurements from these models can streamline preoperative planning, improve future segmentation techniques, and help develop future image-guided or robot-assisted systems for temporal bone procedures.

Automated Registration-Based Temporal Bone Computed Tomography Segmentation for Applications in Neurotologic Surgery.

OBJECTIVE: This study investigates the accuracy of an automated method to rapidly segment relevant temporal bone anatomy from cone beam computed tomography (CT) images. Implementation of this segmentation pipeline has potential to improve surgical safety and decrease operative time by augmenting preoperative planning and interfacing with image-guided robotic surgical systems. STUDY DESIGN: Descriptive study of predicted segmentations. SETTING: Academic institution. METHODS: We have developed a computational pipeline based on the symmetric normalization registration method that predicts segmentations of anatomic structures in temporal bone CT scans using a labeled atlas. To evaluate accuracy, we created a data set by manually labeling relevant anatomic structures (eg, ossicles, labyrinth, facial nerve, external auditory canal, dura) for 16 deidentified high-resolution cone beam temporal bone CT images. Automated segmentations from this pipeline were compared against ground-truth manual segmentations by using modified Hausdorff distances and Dice scores. Runtimes were documented to determine the computational requirements of this method. RESULTS: Modified Hausdorff distances and Dice scores between predicted and ground-truth labels were as follows: malleus (0.100 ± 0.054 mm; Dice, 0.827 ± 0.068), incus (0.100 ± 0.033 mm; Dice, 0.837 ± 0.068), stapes (0.157 ± 0.048 mm; Dice, 0.358 ± 0.100), labyrinth (0.169 ± 0.100 mm; Dice, 0.838 ± 0.060), and facial nerve (0.522 ± 0.278 mm; Dice, 0.567 ± 0.130). A quad-core 16GB RAM workstation completed this segmentation pipeline in 10 minutes. CONCLUSIONS: We demonstrated submillimeter accuracy for automated segmentation of temporal bone anatomy when compared against hand-segmented ground truth using our template registration pipeline. This method is not dependent on the training data volume that plagues many complex deep learning models. Favorable runtime and low computational requirements underscore this method's translational potential.

Chronic Thromboembolic Pulmonary Hypertension: A Comprehensive Review and Multidisciplinary Approach to Surgical Treatment.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed and undertreated sequelae of acute pulmonary embolism. In this comprehensive review, we provide an introductory overview of CTEPH, highlight recent advances in its diagnostic imaging, and describe the surgical technique for pulmonary thromboendarterectomy (PTE), the only established curative treatment for CTEPH. We also discuss the emerging role of balloon pulmonary angioplasty, both independently and combined with PTE, for patients with inoperable, residual, or refractory pulmonary hypertension post PTE. Finally, we stress the importance of a specialized multidisciplinary team approach to CTEPH patient care and share our approach to optimizing care for these patients.

Enantioselective Hydrothiolation: Diverging Cyclopropenes through Ligand Control.

In this article, we advance Rh-catalyzed hydrothiolation through the divergent reactivity of cyclopropenes. Cyclopropenes undergo hydrothiolation to provide cyclopropyl sulfides or allylic sulfides. The choice of bisphosphine ligand dictates whether the pathway involves ring-retention or ring-opening. Mechanistic studies reveal the origin for this switchable selectivity. Our results suggest the two pathways share a common cyclopropyl-Rh(III) intermediate. Electron-rich Josiphos ligands promote direct reductive elimination from this intermediate to afford cyclopropyl sulfides in high enantio- and diastereoselectivities. Alternatively, atropisomeric ligands (such as DTBM-BINAP) enable ring-opening from the cyclopropyl-Rh(III) intermediate to generate allylic sulfides with high enantio- and regiocontrol.

Birinapant Enhances Gemcitabine's Antitumor Efficacy in Triple-Negative Breast Cancer by Inducing Intrinsic Pathway-Dependent Apoptosis.

Triple-negative breast cancer (TNBC) is the most aggressive subgroup of breast cancer, and patients with TNBC have few therapeutic options. Apoptosis resistance is a hallmark of human cancer, and apoptosis regulators have been targeted for drug development for cancer treatment. One class of apoptosis regulators is the inhibitors of apoptosis proteins (IAPs). Dysregulated IAP expression has been reported in many cancers, including breast cancer, and has been shown to be responsible for resistance to chemotherapy. Therefore, IAPs have become attractive molecular targets for cancer treatment. Here, we first investigated the antitumor efficacy of birinapant (TL32711), a biindole-based bivalent mimetic of second mitochondria-derived activator of caspases (SMACs), in TNBC. We found that birinapant as a single agent has differential antiproliferation effects in TNBC cells. We next assessed whether birinapant has a synergistic effect with commonly used anticancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), erlotinib (EGFR inhibitor), and gemcitabine, in TNBC. Among these tested drugs, gemcitabine showed a strong synergistic effect with birinapant. Birinapant significantly enhanced the antitumor activity of gemcitabine in TNBC both in vitro and in xenograft mouse models through activation of the intrinsic apoptosis pathway via degradation of cIAP2 and XIAP, leading to apoptotic cell death. Our findings demonstrate the therapeutic potential of birinapant to enhance the antitumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.