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Cancer early detection and treatment response prediction continue to pose significant challenges. Cancer liquid biopsies focusing on detecting circulating tumor cells (CTCs) and DNA (ctDNA) have shown enormous potential due to their non-invasive nature and the implications in precision cancer management. Recently, liquid biopsy has been further expanded to profile glycoproteins, which are the products of post-translational modifications of proteins and play key roles in both normal and pathological processes, including cancers. The advancements in chemical and mass spectrometry-based technologies and artificial intelligence-based platforms have enabled extensive studies of cancer and organ-specific changes in glycans and glycoproteins through glycomics and glycoproteomics. Glycoproteomic analysis has emerged as a promising tool for biomarker discovery and development in early detection of cancers and prediction of treatment efficacy including response to immunotherapies. These biomarkers could play a crucial role in aiding in early intervention and personalized therapy decisions. In this review, we summarize the significant advance in cancer glycoproteomic biomarker studies and the promise and challenges in integration into clinical practice to improve cancer patient care.

Aversive responses to bright light (photoaversion) require signaling from the eye to the brain. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) encode absolute light intensity and are thought to provide the light signals for photoaversion. Consistent with this, neonatal mice exhibit photoaversion before the developmental onset of image vision, and melanopsin deletion abolishes photoaversion in neonates. It is not well understood how the population of ipRGCs, which constitutes multiple physiologically distinct types (denoted M1-M6 in mouse), encodes light stimuli to produce an aversive response. Here, we provide several lines of evidence that M1 ipRGCs that lack the Brn3b transcription factor drive photoaversion in neonatal mice. First, neonatal mice lacking TRPC6 and TRPC7 ion channels failed to turn away from bright light, while two photon Ca2+ imaging of their acutely isolated retinas revealed reduced photosensitivity in M1 ipRGCs, but not other ipRGC types. Second, mice in which all ipRGC types except for Brn3b-negative M1 ipRGCs are ablated exhibited normal photoaversion. Third, pharmacological blockade or genetic knockout of gap junction channels expressed by ipRGCs, which reduces the light sensitivity of M2-M6 ipRGCs in the neonatal retina, had small effects on photoaversion only at the brightest light intensities. Finally, M1s were not strongly depolarized by spontaneous retinal waves, a robust source of activity in the developing retina that depolarizes all other ipRGC types. M1s therefore constitute a separate information channel between the neonatal retina and brain that could ensure behavioral responses to light but not spontaneous retinal waves.SIGNIFICANCE STATEMENT At an early stage of development, before the maturation of photoreceptor input to the retina, neonatal mice exhibit photoaversion. On exposure to bright light, they turn away and emit ultrasonic vocalizations, a cue to their parents to return them to the nest. Neonatal photoaversion is mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs), a small percentage of the retinal ganglion cell population that express the photopigment melanopsin and depolarize directly in response to light. This study shows that photoaversion is mediated by a subset of ipRGCs, called M1-ipRGCs. Moreover, M1-ipRGCs have reduced responses to retinal waves, providing a mechanism by which the mouse distinguishes light stimulation from developmental patterns of spontaneous activity.

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.

In the central nervous system, melastatin transient receptor potential (TRPM) channels function as receptors for the neurosteroid pregnenolone sulfate (PregS). The expression and function of TRPM3 has been explored in adult retina, although its role during development is unknown. We found, during the second postnatal week in mice, TRPM3 immunofluorescence labeled distinct subsets of inner retinal neurons, including a subset of retinal ganglion cells (RGCs), similar to what has been reported in the adult. Labeling for a TRPM3 promoter-driven reporter confirmed expression of the TRPM3 gene in RGCs and revealed additional expression in nearly all Müller glial cells. Using two-photon calcium imaging, we show that PregS and the synthetic TRPM3 agonist CIM0216 (CIM) induced prolonged calcium transients in RGCs, which were mostly absent in TRPM3 knock-out (KO) mice. These prolonged calcium transients were not associated with strong membrane depolarizations but induced c-Fos expression. To elucidate the impact of PregS-activation of TRPM3 on retinal circuits we took two sets of physiological measurements. First, PregS induced a robust increase in the frequency but not amplitude of spontaneous postsynaptic currents (PSCs). This increase was absent in the TRPM3 KO mice. Second, PregS induced a small increase in cell participation and duration of retinal waves, but this modulation persisted in TRPM3 KO mice, indicating PregS was acting on wave generating circuits independent of TRPM3 channels. Though baseline frequency of retinal waves was slightly reduced in the TRPM3 KO mice, other properties of waves were indistinguishable from wildtype. Together, these results indicate that the presence of neurosteroids impact spontaneous synaptic activity and retinal waves during development via both TRPM3-dependent and independent mechanisms.

In the central nervous system, melastatin transient receptor potential (TRPM) channels function as receptors for the neurosteroid pregnenolone sulfate (PregS). The expression and function of TRPM3 has been explored in adult retina, although its role during development is unknown. We found, during the second postnatal week in mice, TRPM3 immunofluorescence labeled distinct subsets of inner retinal neurons, including a subset of retinal ganglion cells (RGCs), similar to what has been reported in the adult. Labeling for a TRPM3 promoter-driven reporter confirmed expression of the TRPM3 gene in RGCs and revealed additional expression in nearly all Müller glial cells. Using two-photon calcium imaging, we show that PregS and the synthetic TRPM3 agonist CIM0216 (CIM) induced prolonged calcium transients in RGCs, which were mostly absent in TRPM3 knock-out (KO) mice. These prolonged calcium transients were not associated with strong membrane depolarizations but induced c-Fos expression. To elucidate the impact of PregS-activation of TRPM3 on retinal circuits we took two sets of physiological measurements. First, PregS induced a robust increase in the frequency but not amplitude of spontaneous postsynaptic currents (PSCs). This increase was absent in the TRPM3 KO mice. Second, PregS induced a small increase in cell participation and duration of retinal waves, but this modulation persisted in TRPM3 KO mice, indicating PregS was acting on wave generating circuits independent of TRPM3 channels. Though baseline frequency of retinal waves was slightly reduced in the TRPM3 KO mice, other properties of waves were indistinguishable from wildtype. Together, these results indicate that the presence of neurosteroids impact spontaneous synaptic activity and retinal waves during development via both TRPM3-dependent and independent mechanisms.

Detection of ambient illumination in the developing retina prior to maturation of conventional photoreceptors is mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) and is critical for driving several physiological processes, including light aversion, pupillary light reflexes, and photoentrainment of circadian rhythms. The strategies by which ipRGCs encode variations in ambient light intensity at these early ages are not known. Using unsupervised clustering of two-photon calcium responses followed by inspection of anatomical features, we found that the population activity of the neonatal retina could be modeled as six functional groups that were composed of mixtures of ipRGC subtypes and non-ipRGC cell types. By combining imaging, whole-cell recording, pharmacology, and anatomical techniques, we found that functional mixing of cell types is mediated in part by gap junction coupling. Together, these data show that both cell-autonomous intrinsic light responses and gap junction coupling among ipRGCs contribute to the proper encoding of light intensity in the developing retina.

Alexandru Madalin Hasan,1 Simona Cavalu,1 Ahmed Y Kira,2 Rabab S Hamad,3 Mustafa Ahmed Abdel-Reheim,4 Elsayed A Elmorsy,5 Attalla F El-kott,6,7 Kareem Morsy,6,8 Ali S AlSheri,6 Sally Negm,9 Sameh Saber10 1Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, 410087, Romania; 2Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; 3Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia; 4Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia; 5Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, 51452, Saudi Arabia; 6Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia; 7Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt; 8Department of Zoology, Faculty of Science, Cairo University, Cairo, Egypt; 9Department of Life Sciences, College of Science and Art, Mahyel Aseer, King Khalid University, Abha, 62529, Saudi Arabia; 10Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, EgyptCorrespondence: Ahmed Y Kira, Department of Pharmaceutics, Faculty of Pharmacy, ‎Delta University for Science and Technology, Gamasa, Egypt, +11152, Tel +2 01026462867, Fax +2 0502770140, Email ahmed.kira@deltauniv.edu.eg Mustafa Ahmed Abdel-Reheim, Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia, Email m.ahmed@su.edu.saAbstract: Different types of cancers affect the gastrointestinal tract (GIT), starting from the oral cavity and extending to the colon. In general, most of the current research focuses on the systemic delivery of the therapeutic agents, which leads to undesired side effects and a limited enhancement in the therapeutic outcomes. As a result, localized delivery within gastrointestinal (GI) cancers is favorable in overcoming these limitations. However, the localized delivery via oral administration faces many challenges related to the complex structure of GIT (varied pH levels and transit times) as well as the harsh environment within tumor cells (hypoxia, efflux pumps, and acidity). To overcome these obstacles, nano-drug delivery systems (NDDs) have been designed and proved their potential by exploiting these challenges in favor of offering a specific delivery to the desired target. The current review begins with an overview of different GI cancers and their impact globally. Then, it discusses the current treatment approaches and their corresponding limitations. Additionally, the different challenges associated with localized drug delivery for GI cancers are summarized. Finally, the review discusses in detail the recent therapeutic and diagnostic applications of NDDs that have been conducted in oral, esophageal, gastric, colon, and liver cancers, aiming to offer valuable insights into the current and future state of utilizing NDDs for the local treatment of GI cancers. Keywords: gastrointestinal cancer, localized delivery, stimuli-responsive nanomaterials, gastro-retentive delivery systems