Project description:Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) and antibody-drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood-brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC.
Project description:Worldwide gastric cancer remains one of the most common cancers, killing upwards of one million people each year. While the molecular pathogenesis remains unclear, infection with the bacterium Helicobacter pylori is considered a "necessary but not sufficient" cause, not surprisingly as gastric cancer has long been known to be associated with atrophic gastritis. Eradication of H pylori is expected to virtually eliminate gastric cancer and H pylori associated peptic ulcer within approximately 40 years and thus reduce overall mortality. In the USA, the incidence of gastric cancer in the general population is low, reflecting the change in the pattern of gastritis from atrophic to non-atrophic and in the low and decreasing prevalence of H pylori infection in the middle and upper classes. However, the plan for eradication of this important pathogen must be considered within the context of the prevalence and outcome within specific populations.
Project description:Virus-like particles (VLPs) are protein complexes that resemble a virus and constitute highly immunogenic entities as they mimic the pathogen at an important degree. Among nanovaccines, those based on VLPs are the most successful thus far with some formulations already commercialized (e.g., those against hepatitis B and E viruses and human papillomavirus). This chapter highlights the advantages of VLPs-based vaccines, describing approaches for their design and transmittance of the state of the art for mucosal VLPs-based vaccines development. Several candidates have been produced in insect cells, plants, and E. coli and mammalian cells; they have been mainly evaluated in i.n. and oral immunization schemes. i.n. vaccines against the influenza virus and the Norwalk virus are the most advanced applications. For the latter, i.n. formulations are under clinical evaluation. Perspectives for the field comprise the expansion of the use of low-cost platforms such as plants and bacteria, the development of multiepitopic/multivalent vaccines, and computationally designed VLPs. Mucosal VLPs-based vaccines stand as a major promising approach in vaccinology and the initiation of more clinical trials is envisaged in a short time.
Project description:Personalized cancer vaccines (PCVs) are receiving attention as an avenue for cancer immunotherapy. PCVs employ immunogenic peptide epitopes capable of stimulating the immune system to destroy cancer cells with great specificity. Challenges associated with effective delivery of these peptides include poor solubility of hydrophobic sequences, rapid clearance, and poor immunogenicity, among others. The incorporation of peptides into nanoparticles has the potential to overcome these challenges, but the broad range of functionalities found in amino acids presents a challenge to conjugation due to possible interferences and lack of reaction specificity. Herein, a facile and versatile approach to generating nanosized PCVs under mild nonstringent conditions is reported. Following a simple two-step semibatch synthetic approach, amphiphilic hyperbranched polymer-peptide conjugates were prepared by the conjugation of melanoma antigen peptides, either TRP2 (hydrophobic) or MUT30 (hydrophilic), to an alkyne functionalized core via strain-promoted azide-alkyne click chemistry. Self-assembly of the amphiphiles gave spherical nanovaccines (by transmission electron microscopy) with sizes in the range of 10-30 nm (by dynamic light scattering). Fluorescently labeled nanovaccines were prepared to investigate the cellular uptake by antigen presenting cells (dendritic cells), and uptake was confirmed by flow cytometry and microscopy. The TRP2 nanovaccine was taken up the most followed by MUT30 nanoparticles and, finally, nanoparticles without peptide. The nanovaccines showed good biocompatibility against B16-F10 cells, yet the TRP2 peptide showed signs of toxicity, possibly due to its hydrophobicity. A test for immunogenicity revealed that the nanovaccines were poorly immunogenic, implying the need for an adjuvant when administered in vivo. Treatment of mice with melanoma tumors showed that in combination with adjuvant, CpG, groups with the peptide nanovaccines slowed tumor growth and improved survival (up to 24 days, TRP2) compared to the untreated group (14 days).
Project description:Subaortic stenosis secondary to subaortic membrane is the second most common form of left ventricular outflow tract obstruction. We present the case of a 70-year-old male patient who presented with a 6-week history of progressive signs of heart failure. Multimodality imaging was required to confirm the presence of a subaortic membrane. (Level of Difficulty: Beginner.).
Project description:Recently newer synthetic DNA vaccines have been rapidly advanced to clinical study and have demonstrated an impressive degree of immune potency and tolerability. Improvements in DNA delivery over prior needle and syringe approaches include jet delivery, gene gun delivery, among others. Among the most effective of these new delivery methods, advanced electroporation (EP), combined with other advances, induces robust humoral and cellular immunity in both preventative as well as therapeutic studies. Advancements in the design of the DNA inserts include leader sequence changes, RNA and codon optimizations, improved insert designs, increased concentrations of DNA, and skin delivery, appear to complement newer delivery strategies. These advances also provide a framework for the in vivo production of synthetic DNA biologics. In this review, we focus on recent studies of synthetic DNA vaccines in the clinic for the prevention or treatment of infectious diseases with a focus on adaptive electroporation for delivery, and briefly summarize novel preclinical data advancing the in vivo delivery of DNA-encoded antibody-like biologics.
Project description:Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20-25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.
Project description:It is time to shake up public health surveillance. New technologies for sequencing, aided by friction-free approaches to data sharing, could have an impact on public health efforts.
Project description:Persistent infection with high-risk human papillomaviruses (HPVs), such as HPV-16 and HPV-18, can induce cervical cancer in humans. The disease carries high morbidity and mortality among females worldwide. Inoculation with prophylactic HPV vaccines, such as Gardasil® or Cervarix®, is the predominant method of preventing cervical cancer in females 6 to 26 years of age. However, despite the availability of commercial prophylactic HPV vaccines, no therapeutic HPV vaccines to eliminate existing HPV infections have been approved. Peptide-based vaccines, which form one of the most potent vaccine platforms, have been broadly investigated to overcome this shortcoming. Peptide-based vaccines are especially effective in inducing cellular immune responses and eradicating tumor cells when combined with nanoscale adjuvant particles and delivery systems. This review summarizes progress in the development of peptide-based nanovaccines against HPV infection.