Genetic Risk Factors for Idiopathic Urolithiasis: The Causative Role of Genes in Stones Formation

Background: The genetic factor of urolithiasis plays an important role in the etiology. Elucidation of responsible genes can lead to better targeted gene therapy and prevention in the future. This article aims to explain various genetic factors that play a role in kidney stone formation Method: A review article on urolithiasis based on a genetic approach is reported to underlie stone formation. A total of 41 abstracts and research articles published by internationally reputed journals were selected based on the keywords genetic factors and urolithiasis. Summary: A deeper understanding of the genetic factors that play a role in the mechanisms of stone formation and advances in molecular and pharmacogenomics have revolutionized diagnosis and treatment, and paved the way for the identification of new therapeutic targets and treatment approaches based on genetic engineering.

Application of Data Mining in WITMED: Identification of Prognostic Genes in Oral Cancer

In recent years, the booming development of big data, cloud computing, Internet of Things, and other technologies provides conditions for the popularization and application of smart city. The combination of big data and medical information produces the emerging field of WITMED (Wise Information Technology of Med). WITMED is essential for the prospering growth of smart cities, which assumed a high quality of medical service is the most challenging goal for the city government. In this paper, the main attention is paid to the method of targeted gene therapy, which provides a new method for the treatment of oral cancer in inhibiting the growth, differentiation, invasion, and metastasis of oral cancer cells; therefore, the physical and psychological adverse effects of surgery and chemotherapy on patients are reduced and the survival and prognosis of patients are improved. Targeted gene therapy methods need to select the appropriate gene; that is, data mining methods are used to analyze a large number of complex genetic data from smart cities to obtain appropriate genetic markers, which makes the effect of targeted gene therapy better, and also provide some reference for the research of oral cancer gene direction and provide some basis for clinical treatment.

Our Journey Beyond Sunset Boulevard: Evidence-Based Analysis of Tumor-Targeted Cancer Gene Therapy Shines a Critical Spotlight on Long-Term Cancer-Free Survival

This unique “PERSPECTIVE” on Targeted Genetic Medicine for Cancer represents the third manuscript in a series of medical oncology papers by gene therapy pioneers, Gordon and Hall, a combined medical oncologist’s and layman’s trilogy recorded with the following intents and purposes: (i) documenting significant milestones in clinical oncology for the medical community, (ii) honoring forthright principles of “Informed Consent” for the advanced/refractory oncology patient, and (iii) confronting logical fallacies of popular opinion, in light of recent critical analyses of long-term cancer-free survival data. As with the two previous historical “perspectives,” the authors present noteworthy up-to-date clinical research documenting the successful management of refractory metastatic cancers with tumor-targeted gene therapy vectors—validating “Pathotropic” (disease-seeking) tumor targeting Avant la Lettre. This paper provides additional insights into the molecular and cellular mechanisms of both tumor-targeting and tumor-eradication. As with the prior two papers, the authors utilize the revealing powers of allegory and classic literature, adding shared iconic cinematic experiences of postmodernism at times, to educate, inform, and convey the formidable yet verifiable and important hard-core science (that is, the fundamental chemistries, biophysics, molecular biology, genetics, stem cell biology, regulatory biology, synthetic virology, tumor immunology, clinical oncology, bio-pharmacology, histopathology, and cancer gene therapy) embodied within the “smart” therapeutic nanoparticle, DeltaRex-G: a refined “primal-hunter” & “tumor-killer” that actively seeks out the cryptic/hidden “Biochemical (Jailbreak) Signatures” of metastatic cancers, delivers targeted gene therapy “precisely”totumor cells, and ultimately eradicates both primary and metastatic lesions, including lymphatic metastases. Accomplishment of the “DeltaRex-G Rescue-Mission of 2019” with updated FDA regulatory approvals and sustainable/scalable cGMP bioproduction is considered opportune—while the Right-to-Try experimental therapies legislation in the United States comes face-to-face with the U.S. FDA approval of Expanded Access for DeltaRex-G for advanced pancreatic cancer and sarcoma, and compassionate use for all solid tumors—as such, the authors embrace the legitimate rights of the cancer patient to be more fully informed of such beneficial treatments currently available in the United States.

Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies

The natural serotypes of adeno-associated virus (AAV) or their variants, such as AAV8 and AAV5, are commonly used as vectors in the clinical programs for liver-targeted gene therapy. While AAV8 vectors are not highly efficient at targeting primary human hepatocytes, AAV3 vectors have recently demonstrated remarkable efficiency at targeting both human and non-human primate hepatocytes. However, the presence of high levels of neutralizing antibodies (NAbs) impedes transduction into hepatocytes, representing a major obstacle to the clinical application of AAV3 vectors. Herein, we engineered the viral capsid to reduce its reactivity with pre-existing NAbs, thereby enhancing the transduction efficiency. By introducing three substitutions (S472A, S587A, and N706A) on the surface loop of AAV3B capsid protein, we generated a triple mutant AAV3 (AAV.GT5) vector with less reactivity to anti-AAV capsid NAbs. While the transduction efficiency of AAV.GT5 into human hepatocellular cell lines was similar to those of parental AAV3B, it was 50-fold higher for hepatocytes derived from humanized mice compared to AAV8 vectors. Moreover, the AAV.GT5 vector yield was similar to those of the AAV2 and AAV3B vectors. Thus, high resistance to pre-existing NAbs makes AAV.GT5 a promising candidate for future liver-targeted gene therapy clinical trials.

Combined transcriptional, translational and cell surface targeted gene therapy of HER2-positive breast cancer stem cells in three-dimentional cell culture

Purpose Breast Cancer Stem Cells (BCSCs) resist conventional treatments and cause tumor recurrence. Almost 25% of breast cancers overexpress human epidermal growth factor receptor-2 (HER2). Here we developed a novel multi-targeted nanosystem to specifically eradicate HER2-positive BCSCs. Methods Plasmids containing CXCR1 promoter, PE38 toxin and 5′UTR of the basic fibroblast growth factor-2 (bFGF 5'UTR) were constructed. Polyamidoamine (PAMAM) dendrimers functionalized with an anti-HER2 VHH were used for plasmid delivery. Stem proportion of MCF-10A and MDA-MB-231/HER2+ (a cellular model of HER2 overexpression, developed in our lab) were evaluated by mammosphere formation assay. Hanging drop technique was used to produce spheroids. The uptake, gene expression and killing efficacy of the multi-targeted nanosystem were evaluated in both monolayer and spheroid culture. Results MDA-MB-231/HER2+ had more than 3 times higher ability to form mammosphere compared to MCF-10A, representing higher stem proportion in MDA-MB-231/HER2+. In hanging drop culture, MDA-MB-231/HER+ generated compact well-rounded spheroids, while MCF-10A failed to form compact cellular masses. The multi-targeted nanosystem showed much better uptake, higher PE38 expression and subsequent cell death in MDA-MB-231/HER2+ compared to MCF-10A. However efficacy of our targeted toxin gene therapy were lower in MDA-MB-231/HER2+ spheroid than those in monolayer. Conclusions Our novel multi-targeted nanosystem resulted in synergistic cytotoxic effects in HER2-positive BCSCs. This results demonstrate the necessity to use a combinatorial tumor targeting approach, to restrict the expression of a killer gene to target cells. Lower efficacy of our targeted gene therapy in spheroid models vs. monolayer culture suggest that, anticancer therapy assessments using spheroid might be more predictive of clinical efficacy than conventional monolayer culture.

Tumor-targeted gene therapy with lipid nanoparticles inhibits tumor-associated adipocytes and remodels the immunosuppressive tumor microenvironment in triple-negative breast cancer

In breast cancer model, we identified C–C Motif Chemokine Ligand 2 (CCL2) as the key mediator which is secreted by tumor associated adipocytes, and developed targeted lipid-protamine-DNA (LPD) nanoparticles to locally “trap” CCL2 to ameliorate the immunosuppressive tumor microenvironment.