Tumor-Targeted Fluorescence Imaging and Mechanisms of Tumor Cell-Derived Carbon Nanodots

An ideal cancer diagnostic probe should possess precise tumor-targeted accumulation with negligible sojourn in normal tissues. Herein, tumor cell-derived carbon nanodots (C-CNDU87 and C-CNDHepG2) about 3~7 nm were prepared by a solvothermal method with stable fluorescence and negligible cytotoxicity. More interestingly, due to the differences in gene expression of cancers, C-CND structurally mimicked the corresponding precursors during carbonization in which carbon nanodots were functionalized with α-amino and carboxyl groups with different densities on their edges. With inherent homology and homing effect, C-CND were highly enriched in precursor tumor tissues. Mechanistic studies showed that under the mediation of the original configuration of α-amino and carboxyl groups, C-CND specifically bound to the large neutral amino acid transporter 1 (LAT1, overexpressed in cancer cells), achieving specific tumor fluorescence imaging. This work provided a new vision about tumor cell architecture-mimicked carbon nanodots for tumor-targeted fluorescence imaging.

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.

Bacteriophages as Solid Tumor Theragnostic Agents

Cancer, especially the solid tumor sub-set, poses considerable challenges to modern medicine owing to the unique physiological characteristics and substantial variations in each tumor’s microenvironmental niche fingerprints. Though there are many treatment methods available to treat solid tumors, still a considerable loss of life happens, due to the limitation of treatment options and the outcomes of ineffective treatments. Cancer cells evolve with chemo- or radiation-treatment strategies and later show adaptive behavior, leading to failed treatment. These challenges demand tailored and individually apt personalized treatment methods. Bacteriophages (or phages) and phage-based theragnostic vectors are gaining attention in the field of modern cancer medicine, beyond their bactericidal ability. With the invention of the latest techniques to fine-tune phages, such as in the field of genetic engineering, synthetic assembly methods, phage display, and chemical modifications, noteworthy progress in phage vector research for safe cancer application has been realized, including use in pre-clinical studies. Herein, we discuss the distinct fingerprints of solid tumor physiology and the potential for bacteriophage vectors to exploit specific tumor features for improvised tumor theragnostic applications.

Bioprinting the Tumor Microenvironment with an Upgraded Consumer Stereolithographic 3D Printer

A widespread application of three-dimensional (3D) bioprinting in basic and translational research requires the accessibility to affordable printers able to produce physiologically relevant tissue models. To facilitate the use of bioprinting as a standard technique in biology, an open-source device based on a consumer-grade 3D stereolithographic (SL) printer was developed. This SL bioprinter can produce complex constructs that preserve cell viability and recapitulate the physiology of tissues. The detailed documentation of the modifications apported to the printer as well as a throughout performance analysis allow for a straightforward adoption of the device in other labs and its customization for specific applications. Given the low cost, several modified bioprinters could be simultaneously operated for a highly parallelized tissue production. To showcase the capability of the bioprinter, we produced constructs consisting of patient-derived cholangiocarcinoma organoids encapsulated in a gelatin methacrylate (GelMA)/polyethylene glycol diacrylate (PEGDA) hydrogel. A thorough characterization of different GelMA/PEGDA ratios revealed that the mechanical properties of the bioprinted tumor model can be accurately fine-tuned to mimic a specific tumor micro-environment. Immunofluorescence and gene expression analyses of tumor markers confirmed that the bioprinted synthetic hydrogel provides a flexible and adequate replacement of animal-derived reconstituted extracellular matrix.

Novel Molecular Targets for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, only a few treatments are available, most of which are effective only for the early stages of the disease. Therefore, there is an urgent needing for potential markers for a specifically targeted therapy. Candidate proteins were selected from datasets of The Human Protein Atlas, in order to identify specific tumor-associated proteins overexpressed in HCC samples associated with poor prognosis. Potential epitopes were predicted from such proteins, and homology with peptides derived from viral proteins was assessed. A multiparametric validation was performed, including recognition by PBMCs from HCC-patients and healthy donors, showing a T-cell cross-reactivity with paired epitopes. These results provide novel HCC-specific tumor-associated antigens (TAAs) for immunotherapeutic anti-HCC strategies potentially able to expand pre-existing virus-specific CD8+ T cells with superior anticancer efficacy.

Broad misappropriation of developmental splicing profile by cancer in multiple organs

Oncogenesis mimics key aspects of embryonic development. However, the underlying molecular determinants are not completely understood. Leveraging temporal transcriptomic data during development in multiple human organs, we demonstrate that the 'embryonic positive (EP)' alternative splicing events, specifically active during human organogenesis, are broadly reactivated in the organ-specific tumor. EP events are associated with key oncogenic processes and their reactivation predicts proliferation rates in cancer cell lines as well as patient survival. EP exons are significantly enriched for nitrosylation and transmembrane domains coordinately regulating splicing in multiple genes involved in intracellular transport and N-linked glycosylation respectively, known critical players in cancer. We infer critical splicing factors (CSF) potentially regulating these EP events and show that CSFs exhibit copy number amplifications in cancer and are upregulated specifically in malignant cells in the tumor microenvironment. Mutational inactivation of CSFs results in decreased EP splicing, further supporting their causal role. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of CSFs in brain and liver, which can be potentially targeted using FDA approved drugs. Our study provides the first comprehensive demonstration of a splicing-mediated link between development and cancer, and suggest novel targets including splicing events, splicing factors, and transcription factors.

ROLE OF ACCESS OSTEOTOMY IN HEAD AND NECK LESIONS – A REVIEW

The surgical resection of the head and neck lesions summarizes the principles, classifications, applications, complications, and post-operative care of osteotomy with the standard protocols performed safely. It often poses a great surgical challenge due to the anatomical complexity, difficulty in accessibility, and proximity of vital structures. A multidisciplinary approach is often required in these situations for their better exposure to provide surgical access. Access osteotomy is the choice and type for these head and neck lesions, which are most often based on the anatomic extent of the lesion, vascularity of the lesion, and involvement of neurovascular structures in and around it. The literature search using Medline from the year 1986 to 2019 were performed and textbooks were also collected by hand search from the same period. The role of aggressive surgical resection has not been established for malignant head and neck lesions with the technical feasibility and its efficacy for specific tumor types must be defined by the future studies. Thus, we would like to conclude that access osteotomy allows the surgeon a better view and an access of the surgical field to resect the tumor completely with safer margins, preserving the vital structures, pre-operative functions, and reducing post-operative complications.

Computational modeling of schedule-specific chemotherapy outcomes in mouse tumor model

Despite the rapid development of new innovative strategies in cancer treatment like immunotherapy, chemotherapy still remains a common choice in many cases. Standard protocols of chemotherapeutic administration rely on a maximal tolerated dose paradigm, however there is growing evidence that this approach is not always optimal. Alternative scheduling, like metronomic - low dose continuous drug administration - were recently proved their efficacy. The space of available variants of drug administration protocols is prohibitively large to be explored empirically, and there is an urgent need of predictive mathematical models for rational chemotherapeutic scheduling design. In this work we tested the ability of the minimal pharmacokinetic-pharmacodynamics model to describe schedule-specific tumor volume time evolution in different mouse tumor models.

Case series study: the diagnosis and treatment of fifty tumors and pseudotumors at the proximal femur

Introduction: Tumor and pseudotumor (TP) at the proximal femur (PF) can seriously affect mortality, extremity function, and body integrity. However, reports often focused on a specific tumor, not regional lesions. This study focuses on clinical findings, imaging, micro-pathology, and the treatment of all TP at the site. Methods: The study involved all patients who had a confirmed tumor or pseudotumor diagnosis at the PF. The clinical findings, X-ray, and biopsy were recorded and analyzed. Treatment was optional depending on the patient's situation and available condition of the hospital. The functional outcome, bone healing were defined at the last examination or two years of follow-up. Results: Fifty patients were involved in the study. Twenty-four patients had apparent tumors. TP at the PF, neck-trochanter, trochanters, and neck were 21 (42%), 16 (32%), 9 (18%), and 4 (8%) cases, respectively. There were 29 (58%) pathologic fractures. Biopsy was made for all patients. Twenty-three cases (46%) were malignant, and 8 (16%) cases were giant cell tumors. Thirtythree patients suffered from an operation. Ennerking's functional score was excellent, good, fair, and poor in 24 (48%), 5 (10%), 1 (2%), and 20 (40%) patients, respectively. For the last outcomes of 33 operated patients, 17 healed, three unchanged, one worse, and two dead. Conclusions: For the PF TP, the rate of malignant and pathological fracture was high. The giant cell tumor was not rare. The resection of the TP combined with grafts using ordinary fixation devices was satisfactory.

Patient-Specific Tumor Microenvironment Models

The heterogeneity of cancer makes it difficult to predict the prognosis of treatment. There is still a lack of preclinical model systems that reflect the clinical characteristics of patients who have heterogenetic tumors. Advances in 3-dimentional (3D) cell culture are leading to discoveries that occur in the development and progression of cancer that has not been known. There are many models including patient-derived xenograft, patient-derived organoid and spheroid, patient-derived explant, scaffold-based model, and system-based model. Each 3D model has its strengths and limitations. One model cannot answer every question, so it seems most reasonable to approach multiple models when studying cancer heterogeneity. Hopefully, 3D tumor modeling will make tremendous progress on this path by fusion of innovative biomaterials and advanced modeling techniques that can partially mimic the heterogeneous environment of real tumors.