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Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683). High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

BackgroundCD47 is a broadly expressed cell surface glycoprotein associated with immune evasion. Interaction with the inhibitory receptor signal regulatory protein alpha (SIRPα), primarily expressed on myeloid cells, normally serves to restrict effector function (eg, phagocytosis and immune cell homeostasis). CD47/SIRPα antagonists, commonly referred to as ‘macrophage checkpoint’ inhibitors, are being developed as cancer interventions. SRF231 is an investigational fully human IgG4 anti-CD47 antibody that is currently under evaluation in a phase 1 clinical trial. The development and preclinical characterization of SRF231 are reported here.MethodsSRF231 was characterized in assays designed to probe CD47/SIRPα blocking potential and effects on red blood cell (RBC) phagocytosis and agglutination. Additionally, SRF231-mediated phagocytosis and cell death were assessed in macrophage:tumor cell in vitro coculture systems. Further mechanistic studies were conducted within these coculture systems to ascertain the dependency of SRF231-mediated antitumor activity on Fc receptor engagement vs CD47/SIRPα blockade. In vivo, SRF231 was evaluated in a variety of hematologic xenograft models, and the mechanism of antitumor activity was assessed using cytokine and macrophage infiltration analyses following SRF231 treatment.ResultsSRF231 binds CD47 and disrupts the CD47/SIRPα interaction without causing hemagglutination or RBC phagocytosis. SRF231 exerts antitumor activity in vitro through both phagocytosis and cell death in a manner dependent on the activating Fc-gamma receptor (FcγR), CD32a. Through its Fc domain, SRF231 engagement with macrophage-derived CD32a serves dual purposes by eliciting FcγR-mediated phagocytosis of cancer cells and acting as a scaffold to drive CD47-mediated death signaling into tumor cells. Robust antitumor activity occurs across multiple hematologic xenograft models either as a single agent or in combination with rituximab. In tumor-bearing mice, SRF231 increases tumor macrophage infiltration and induction of the macrophage cytokines, mouse chemoattractant protein 1 and macrophage inflammatory protein 1 alpha. Macrophage depletion results in diminished SRF231 antitumor activity, underscoring a mechanistic role for macrophage engagement by SRF231.ConclusionSRF231 elicits antitumor activity via apoptosis and phagocytosis involving macrophage engagement in a manner dependent on the FcγR, CD32a.

Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.Claire Patterson et al. present the design and development of AZD0466, a drug-dendrimer conjugate, and use preclinical and mathematical models to determine the optimal release rate of the drug from the dendrimer carrier for maximal therapeutic index in terms of anti-tumour efficacy and cardiovascular tolerability. This study identifies this promising dual Bcl-2/Bcl-xL inhibitor for progression to clinical development.

Background Immune checkpoint blockade of CD47 has shown promising results in lymphoid malignancies, with its effects attributed to enabling tumor-cell phagocytosis. However, alternate cytotoxic cell death mechanisms have been reported, potentially contributing to the overall anti-tumor activity. Although previous studies have highlighted a mechanism of caspase-independent cell death, this mechanism has yet to be well-characterized, thereby warranting further investigation to comprehensively understand the anti-tumor mechanism of CD47 blockade to facilitate optimal drug partner selection for combination therapy. Methods The fully humanized anti-CD47 monoclonal antibodies, SRF231, magrolimab, as well as a mouse monoclonal anti-CD47 antibody, B6H12, were used. Multiple cell death mechanisms were evaluated including apoptosis, autophagy and necroptosis by using customized Hoechst/Annexin V, the precision medicine technique BH3 profiling, as well as standard experimental techniques – flow cytometry, siRNA and CRISPR Cas9 genetic manipulation, Western blotting, and immunohistochemistry. These techniques were used on a comprehensive range of lymphoid malignant models including diffuse large B-cell lymphoma, Burkitt lymphoma, and T-acute lymphoblastic leukemia cell lines, patient primary chronic lymphocytic leukemia cells, as well as lymphoid cell-line derived and patient-derived xenograft mice, to elucidate the mechanism of cell death by CD47 blockade and to identify the optimal drug partners for treatment combination. Results We demonstrate that the anti-CD47 antibodies SRF231, magrolimab, and B6H12 eliminated tumor cells from various in vitro and in vivo lymphoid malignant models via the activation of the RIPK1/MLKL/necroptotic pathway. Moreover, the BH3 profiling technique distinguished two different lymphoid malignant models that respond differently to the BCL-2 inhibitor venetoclax when combined with SRF231; one highlighting the effective yet distinct mechanisms of SRF231-induced necroptosis and venetoclax-induced apoptosis in models that were specifically and/or highly dependent on BCL-2 for survival, while the other implicating venetoclax as a counterproductive partner with SRF231 in models that were not dependent on BCL-2 for survival or were not responsive to venetoclax treatment. Conclusion Collectively, this study unravels a novel, non-canonical cell death mechanism of targeting CD47 by activating necroptosis, and provides evidence and rationale for further evaluation of a therapeutic strategy of combining CD47 blockade with and without apoptotic inducers for suitable patients with lymphoid malignancies. Graphical Abstract

Visual-based obstacle detection from an autonomous surface vessel (ASV) is a complex task due to high variance of scene properties such as different illumination and presence of reflections. One approach in implementing the task is through extracting waterlines to enable inferring of vessel orientation and obstacles presence. Classical computer vision algorithms for detection holds limitation in robustness and scalability. With recent breakthroughs in deep neural network architectures, vision-based object detection is seen to obtain high performance. In this work, the deep learning models based on Convolutional Neural Network (CNN) to implement binary semantic segmentation is studied. This architecture identifies each pixel to water and non-water classes. In purpose of benchmarking models, Fully Convolutional Network (FCN), SegNet and U-Net are trained on a publicly available dataset, IntCatch Vision Data Set (ICVDS), to evaluate the performance. From the experiments carried out, quantitative results show effectiveness of the models with accuracy all above 95.55% and lowest average speed of 11 frames per second. To improve, pre-trained networks (VGG 16, Resnet-50 and MobileNet) are used as a backbone, obtaining an improved accuracy above 98.14% with lowest inferring speed of 10 frame per second. Using the developed ASV, new dataset of 143 images called Malaysia ASV Dataset (MASVD) is collected, labelled and made publicly available. The trained models are tested with the newly collected dataset obtaining accuracy of 75%. The high accuracy performance shows potential for the models to be employed for collision avoidance algorithm in ASV navigation.

Five million neurosurgical cases go untreated each year. This is in part due to the lack of neurosurgical care providers. The World Federation of Neurosurgical Societies has spearheaded efforts to monitor the number of neurosurgical providers around the globe since 2016. In this perspective, we discuss why, when, and how the neurosurgical workforce should be measured.

Spinal epidural abscess (SEA) is a rare and potentially devastating neurologic disease that is commonly treated with neurosurgical decompression and evacuation. We describe the case of an 11-month-old immunocompetent infant who presented with a large multiloculated methicillin-resistant abscess in the left lung apex with likely mediastinal involvement, extending into the epidural space from C7 down to L2 causing cord compression which was successfully treated with percutaneous placement of an epidural drainage catheter and antibiotic therapy. Although there are rare reports of percutaneous drainage of SEAs, to our knowledge, there are no reports of successful use of percutaneous indwelling catheters resulting in the complete resolution of an SEA. Holo-spinal epidural abscess in an infant is an extremely rare disease with limited literature available regarding the best practice for its treatment. Multiple considerations must be taken into account when weighing the different treatment options ranging from surgical decompression to conservative management with antibiotic therapy. We present a unique case of successful treatment with percutaneous epidural drain placement. This provides a reasonable alternative for management in children for whom surgical decompression carries multiple risks for complications both acutely and delayed.

Diabetic retinopathy is the most common complications of diabetes mellitus that, in most occasions, lead to blindness. Multiple evidences linked the serum magnesium, iron and ferritin disturbance with diabetes and its complications. A case–control study was conducted at Makkah Eye Complex, Khartoum, Sudan, to compare the levels of serum magnesium, iron and ferritin in patients with diabetic retinopathy with diabetic patients without diabetic retinopathy (controls). Findings indicate that all patients had type 2 diabetes. The two groups (50 in each arm) were well matched in their basic characteristics. Median (25th–75th interquartile) of serum magnesium in patients with diabetic retinopathy were significantly lower than patients without diabetic retinopathy [1.48 (0.75–1.64) vs. 1.92 (1.4–2.3)mg/dl, P  = 0.022]. The median of serum iron and ferritin were lower in cases than control group but did not reach a statistical significance [20.5 (17.2–48.0) vs. 27.0 (16.0–54.0) μg/dl, P  = 0.568; 98.0 (45.0–134.75) vs. 101.0 (47.0–161.0) μg/l, P  = 0.818]. The duration of diabetes [16.5 (9.3) vs. 11.2 (6.6) years; P  = 0.014] and haemoglobin level [13.7 (0.9) vs. 12.5 (2.0) g/dl; P  = 0.039] were significantly higher in cases group than control group. A significant inverse correlation was observed between serum magnesium and iron levels. Twenty (40 %) patients had severe non-proliferative diabetic retinopathy with mild macular edema, which is the most prevalent type among the cases group. Hypomagnesaemia among diabetic patients was associated with diabetic retinopathy, while serum iron and ferritin have no significant effect in this setting. Severe non-proliferative diabetic retinopathy with mild macular edema is the prevalent type in this study.

Background: Follicular dendritic cell (FDC) sarcoma is an extremely rare neoplasm, which has only been reported once in the literature with an intracranial occurrence. Neither hemorrhagic presentation of an intracranial instance of FDC sarcoma nor its rapid recurrence has yet been published in the literature. Case Description: We report the case of a 61-year-old female who presented with confusion and headaches secondary to a right frontal hemorrhagic lesion, and her subsequent presentations for recurrence of the lesion and finding of a new intracranial lesion. Immunohistopathologic analysis confirmed the diagnosis based on immunoreactivity for clusterin and CD 35. Conclusion: As demonstrated in this case report, the presentation and progression of primary intracranial follicular dendritic cell sarcoma can often be misleading, and consideration for this rare entity should be made in cases of hemorrhagic dural-based lesions without a primary source of malignancy.

Purpose To quantify the safety and utility of biopsy of pediatric diffuse midline glioma (DMG). Methods This study was conducted in accordance with PRISMA guidelines. PubMed, Embase, Scopus, and Web of Science were queried for relevant articles from inception until June 2023. Two reviewers identified all articles that included diagnostic yield, morbidity, and mortality rates for pediatric DMG patients. Studies that did not present original data or were not in English or peer-reviewed were excluded. Meta-analysis was conducted in R using Freeman-Tukey or logit transformation and DerSimonian-Laird random-effects models. The risk of bias was assessed using the Newcastle–Ottawa Scale. A protocol for this review was not registered. Results We identified 381 patients from ten studies that met all criteria. DMG biopsy is safe overall (0% mortality, 95% CI: 0–0.6%; 11.0% morbidity, 95% CI: 4.8–18.9%) and has a high diagnostic yield (99.9%, 95% CI: 98.5–100%). The use of stereotactic biopsy is a significant moderator of morbidity ( p  = 0.0238). Molecular targets can be identified in approximately 53.4% of tumors (95% CI: 37.0–69.0%), although targeted therapies are only delivered in about 33.5% of all cases (95% CI: 24.4–44.1%). Heterogeneity was high for morbidity and identification of targets. The risk of bias was low for all studies. Conclusion We conducted the first meta-analysis of DMG biopsy to show that it is safe, effective, and able to identify relevant molecular targets that impact targeted therapy.