Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Jan 23

Zhang, Y;Tacheva-Grigorova, SK;Sutton, J;Melton, Z;Mak, YSL;Lay, C;Smith, BA;Sai, T;Van Blarcom, T;Sasu, BJ;Panowski, SH;
PMID: 36692420 | DOI: 10.1158/1078-0432.CCR-22-2293

Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications.A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells.A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated.In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.

Nociception and pain in humans lacking functional TRPV1 channel

The Journal of clinical investigation

2022 Dec 01

Katz, B;Zaguri, R;Edvardson, S;Maayan, C;Elpeleg, O;Lev, S;Davidson, E;Peters, M;Kfir-Erenfeld, S;Berger, E;Ghazalin, S;Binshtok, AM;Minke, B;
PMID: 36454632 | DOI: 10.1172/JCI153558

Chronic-pain is a debilitating illness that has become exceedingly widespread with currently limited treatments. Differences in the molecular signature of nociceptors, have been demonstrated between human and the commonly-used mouse model, suggesting functional differences in detection and transmission of noxious-stimuli. Therefore, direct understanding of pain-physiology in humans is required for pain treatment. This could be facilitated by studying humans carrying deleterious genetic mutations affecting pain sensation. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with several body-functions, in particular, noxious-heat detection and inflammatory-pain. Reports of adverse effects in human trials have hinder the clinical development of TRPV1 antagonists as novel pain relievers. Hence, studies on the functional roles of TRPV1, which currently rely mainly on evidences obtained from rodents, should be extended to humans. Here, we examined humans carrying a unique missense mutation in TRPV1, rendering the channel non-functional. The affected individual demonstrated lack of aversion towards capsaicin and elevated heat-pain threshold. Surprisingly, he showed elevated cold-pain threshold and extensive neurogenic inflammatory flare and pain-responses following application of the TRPA1 channel-activator, mustard-oil. Our study provides the first direct evidence for pain-related functional-changes linked to TRPV1 in humans, which is a prime target in the development of novel pain-relievers.

Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets

Molecules (Basel, Switzerland)

2022 Nov 28

Fan, X;Lu, Y;Du, G;Liu, J;
PMID: 36500386 | DOI: 10.3390/molecules27238296

TWIK-related acid-sensitive K+ (TASK) channels, including TASK-1, TASK-3, and TASK-5, are important members of the two-pore domain potassium (K2P) channel family. TASK-5 is not functionally expressed in the recombinant system. TASK channels are very sensitive to changes in extracellular pH and are active during all membrane potential periods. They are similar to other K2P channels in that they can create and use background-leaked potassium currents to stabilize resting membrane conductance and repolarize the action potential of excitable cells. TASK channels are expressed in both the nervous system and peripheral tissues, including excitable and non-excitable cells, and are widely engaged in pathophysiological phenomena, such as respiratory stimulation, pulmonary hypertension, arrhythmia, aldosterone secretion, cancers, anesthesia, neurological disorders, glucose homeostasis, and visual sensitivity. Therefore, they are important targets for innovative drug development. In this review, we emphasized the recent advances in our understanding of the biophysical properties, gating profiles, and biological roles of TASK channels. Given the different localization ranges and biologically relevant functions of TASK-1 and TASK-3 channels, the development of compounds that selectively target TASK-1 and TASK-3 channels is also summarized based on data reported in the literature.

News from around the RNA world: new avenues in RNA biology, biotechnology and therapeutics from the 2022 SIBBM meeting

Biology open

2022 Oct 15

Brancato, V;Brentari, I;Coscujuela Tarrero, L;Furlan, M;Nicassio, F;Denti, MA;
PMID: 36239357 | DOI: 10.1242/bio.059597

Since the formalization of the Central Dogma of molecular biology, the relevance of RNA in modulating the flow of information from DNA to proteins has been clear. More recently, the discovery of a vast set of non-coding transcripts involved in crucial aspects of cellular biology has renewed the enthusiasm of the RNA community. Moreover, the remarkable impact of RNA therapies in facing the COVID19 pandemics has bolstered interest in the translational opportunities provided by this incredible molecule. For all these reasons, the Italian Society of Biophysics and Molecular Biology (SIBBM) decided to dedicate its 17th yearly meeting, held in June 2022 in Rome, to the many fascinating aspects of RNA biology. More than thirty national and international speakers covered the properties, modes of action and applications of RNA, from its role in the control of development and cell differentiation to its involvement in disease. Here, we summarize the scientific content of the conference, highlighting the take-home message of each presentation, and we stress the directions the community is currently exploring to push forward our comprehension of the RNA World 3.0.

In vivo transcriptomic profiling using cell encapsulation identifies effector pathways of systemic aging

eLife

2022 Mar 04

Mashinchian, O;Hong, X;Michaud, J;Migliavacca, E;Lefebvre, G;Boss, C;De Franceschi, F;Le Moal, E;Collerette-Tremblay, J;Isern, J;Metairon, S;Raymond, F;Descombes, P;Bouche, N;Muñoz-Cánoves, P;Feige, JN;Bentzinger, CF;
PMID: 35245177 | DOI: 10.7554/eLife.57393

Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here, we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence, and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy.

Microglia Are Involved in Regulating Histamine Dependent and Non-Dependent Itch Transmissions With Distinguished Signal Pathways

SSRN Electronic Journal

2022 Jul 23

Yang, Y;Mou, B;Zhao, H;Yun, X;Xiong, M;Liu, Y;Pan, H;Ma, C;Li, B;Peng, J;
| DOI: 10.2139/ssrn.4164239

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ central microglia and peripheral macrophages together (whole depletion), or selectively deplete central microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results indicated that central microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

The Role of Nerve Fibers in the Tumor Immune Microenvironment of Solid Tumors

Advanced biology

2022 Jun 25

Hernandez, S;Serrano, AG;Solis Soto, LM;
PMID: 35751462 | DOI: 10.1002/adbi.202200046

The importance of neurons and nerve fibers in the tumor microenvironment (TME) of solid tumors is now acknowledged after being unexplored for a long time; this is possible due to the development of new technologies that allow in situ characterization of the TME. Recent studies have shown that the density and types of nerves that innervate tumors can predict a patient's clinical outcome and drive several processes of tumor biology. Nowadays, several efforts in cancer research and neuroscience are taking place to elucidate the mechanisms that drive tumor-associated innervation and nerve-tumor and nerve-immune interaction. Assessment of neurons and nerves within the context of the TME can be performed in situ, in tumor tissue, using several pathology-based strategies that utilize histochemical and immunohistochemistry principles, hi-plex technologies, and computational pathology approaches to identify measurable histopathological characteristics of nerves. These features include the number and type of tumor associated nerves, topographical location and microenvironment of neural invasion of malignant cells, and investigation of neuro-related biomarker expression in nerves, tumor cells, and cells of the TME. A deeper understanding of these complex interactions and the impact of nerves in tumor biology will guide the design of better strategies for targeted therapy in clinical trials.

BS20 Dexamethasone inhibits opn-activation associated with intimal hyperplasia in vein grafts

Basic science

2022 Jun 01

McQueen, L;Ladak, S;Tavares, A;Murphy, G;Zakkar, M;
| DOI: 10.1136/heartjnl-2022-bcs.200

BACKGROUND The long saphenous vein (LSV) is commonly utilised in CABG surgery to facilitate revascularisation. However, over time these grafts develop intimal hyperplasia (IH) and accelerated atherosclerosis, leading to stenosis and occlusion. A common feature of IH is vascular calcification (VC) within the affected vessel. Recently, the matricellular protein osteopontin (OPN) has been implicated in this process at endothelial injury sites in porcine models, but this has not been expanded to humans. Consecutively, studies have implicated the arterial haemodynamic environment as a major driver of the pro-inflammatory conditions facilitating VC and IH. As such, treatment with a synthetic glucocorticoid, dexamethasone, which has proven beneficial in inhibiting IH in murine models, may beneficially modulate this process in humans. This work aims to assess the role of OPN on VC and IH in an ex vivo model, whether dexamethasone can modulate this process, and whether detection of VC in situ can act as a novel clinical monitoring approach to graft patency.

Multiple follicular abnormalities in a 1-year old cat consistent with basaloid follicular hamartomas

Veterinary dermatology

2022 Mar 16

Moog, F;Demorieux, V;Gaide, N;Semin, MO;Abadie, J;Zacharopoulou, M;Marinovic, L;Delverdier, M;Degorce-Rubiales, F;Cadiergues, MC;
PMID: 35297135 | DOI: 10.1111/vde.13064

In humans, basaloid follicular hamartomas are benign follicular tumours, that can be solitary or multiple, in which case they show autosomal dominant inheritance.This study describes clinical and histopathological findings observed in a young cat, which could be consistent with basaloid follicular hamartomas.Multiple follicular abnormalities, consistent with cutaneous diffuse basaloid follicular hamartomas, were observed in skin samples from a one-year old neutered domestic short hair cat. Clinical signs were diffuse symmetrical alopecia with exaggerated skin markings (ventral abdomen, thorax and medial aspects of the limbs) and intense follicular-centred thickening (face and feet). Microscopic lesions were characterised by multiple proliferative follicular abnormalities in all samples. The epidermis showed a very irregular surface with the follicles filled with variably pigmented keratin. The epithelial walls of the follicles had multiple small hyperplastic basaloid cells foci. In the superficial dermis under the epidermis and around the follicles, fibroblastic spindle-shaped mesenchymal cells with a homogeneous moderate density were present in the collagenous connective tissue. The interfollicular epidermis was also abnormal with multiple small proliferating trichoblastic foci originating from the basal layer. RNAscope testing for feline papillomavirus was negative.This case report provides the first evidence of clinical and histopathological findings of multiple follicular abnormalities, consistent with cutaneous diffuse basaloid follicular hamartomas in a cat.

An Enriched Environment Reduces Chronic Stress-Induced Visceral Pain Through Modulating Microglial Activity in the Central Nucleus of the Amygdala

American journal of physiology. Gastrointestinal and liver physiology

2021 Dec 08

Yuan, T;Orock, A;Greenwood-Van Meerveld, B;
PMID: 34877892 | DOI: 10.1152/ajpgi.00307.2021

Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders, however, the underlying mechanisms of CBT remain to be explored. Previously we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We sterotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days following CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment and the expression of synaptic pruning-related signals C1q, C3 and C3R were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared to control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity.

Circulating Monocytes Associated with Anti-PD-1 Resistance in Human Biliary Cancer Induce T Cell Paralysis

SSRN Electronic Journal

2021 Dec 21

Keenan, B;McCarthy, E;Ilano, A;Yang, H;Zhang, L;Allaire, K;Fan, Z;Li, T;Lee, D;Sun, Y;Cheung, A;Luong, D;Chang, H;Marquez, J;Sheldon, B;Kelley, R;ye, j;Fong, L;
| DOI: 10.2139/ssrn.3985187

Although suppressive myeloid cells have been proposed as a mechanism of resistance to immunotherapy, their role in response to checkpoint inhibitor treatment (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), is largely unknown. We used multiplexed single-cell transcriptomic and epitope sequencing to profile >200,000 peripheral blood mononuclear cells from advanced BTC. In BTC patients, CD14+ monocytes expressing high levels of immunosuppressive cytokines and trafficking molecules involved in chemotaxis (CD14CTX) are associated with resistance to CPI. CD14CTX can directly suppress CD4+ T cells and induce SOCS3 expression in naive CD4+ T cells rendering them functionally unresponsive. Gene signatures from CD14CTX are correlated with worse survival in BTC patients as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising in the setting of anti-PD-1 insensitivity can induce T cell paralysis as a distinct mode of tumor-mediated immunosuppression.

Innovations in Placental Pathology

Benirschke's Pathology of the Human Placenta

2021 Dec 08

Pantham, P;Soncin, F;Zhang-Rutledge, K;Srinivasan, S;Lamale-Smith, L;Laurent, L;Parast, M;
| DOI: 10.1007/978-3-030-84725-8_31

Over the past two decades, multiple new methods have been developed for probing the structure and function of human tissues and organ systems. These innovative methods have paved the road toward a new era in medicine, where diseases are subclassified, not only based on histology but also at the molecular level, and often based on an integrated assessment of clinical signs and symptoms, detailed in vivo imaging, and histologic and molecular evaluation of biopsied tissues. Advances in detection, identification, and quantification of both cell-free and extracellular vesicle-derived biomarkers in the blood are more commonly allowing for noninvasive measures of organ function, precluding the need for invasive biopsies. In addition, stem cells, “organoids,” and “organ-on-a-chip” models have permitted the study of human cells and tissues in greater detail and complexity. The application of these innovative methods to the human placenta is detailed in this chapter, highlighting not only the new information gained about the structure and function of this important transient organ but also the ways in which this information can be translated into, and thus transform, the practice of placental pathology.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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