Fundamentals and Applications of Focused Ultrasound-Assisted Cancer Immune Checkpoint Inhibition for Solid Tumors.

Despite spectacular clinical successes across several cancer types, immune checkpoint inhibition is effective only in subgroups of patients and suffers from significant systemic toxicities, highlighting the need to understand and locally overcome the mechanisms of therapeutic resistance. Similarly to other therapeutics, immunotherapies face delivery challenges (for example, antibodies need to reach their targets) and immunological barriers that are unique to solid tumors and their microenvironment. Interestingly, focused ultrasound (FUS), with or without microbubbles, which has been shown to enhance gene and drug delivery, notably in oncology, has been recently found to trigger immunological responses. In recent years, there has been a strong emphasis on understanding the biological and immunological effects of FUS for cancer therapy, and FUS is now emerging as an approach that can improve cancer immunotherapy. We herein review: (1) the immunological barriers implicated in ICI resistance; (2) the fundamentals of FUS +/- MB and the current knowledge on leveraging FUS +/- MB bioeffects for improving ICI therapy efficacy; (3) the immune profile of tumor models that have been successfully treated with FUS and ICI; and finally, (4) we discuss the challenges ahead for translating FUS and MB treatments to the clinic, highlighting the exciting perspectives for this new research area.

Stimuli-responsive biomaterials: smart avenue toward 4D bioprinting.

3D bioprinting is an advanced technology combining cells and bioactive molecules within a single bioscaffold; however, this scaffold cannot change, modify or grow in response to a dynamic implemented environment. Lately, a new era of smart polymers and hydrogels has emerged, which can add another dimension, e.g., time to 3D bioprinting, to address some of the current approaches' limitations. This concept is indicated as 4D bioprinting. This approach may assist in fabricating tissue-like structures with a configuration and function that mimic the natural tissue. These scaffolds can change and reform as the tissue are transformed with the potential of specific drug or biomolecules released for various biomedical applications, such as biosensing, wound healing, soft robotics, drug delivery, and tissue engineering, though 4D bioprinting is still in its early stages and more works are required to advance it. In this review article, the critical challenge in the field of 4D bioprinting and transformations from 3D bioprinting to 4D phases is reviewed. Also, the mechanistic aspects from the chemistry and material science point of view are discussed too.

Engineered Biomimetic Membranes for Organ-on-a-Chip.

Organ-on-a-chip (OOC) systems are engineered nanobiosystems to mimic the physiochemical environment of a specific organ in the body. Among various components of OOC systems, biomimetic membranes have been regarded as one of the most important key components to develop controllable biomimetic bioanalysis systems. Here, we review the preparation and characterization of biomimetic membranes in comparison with the features of the extracellular matrix. After that, we review and discuss the latest applications of engineered biomimetic membranes to fabricate various organs on a chip, such as liver, kidney, intestine, lung, skin, heart, vasculature and blood vessels, brain, and multiorgans with perspectives for further biomedical applications.

Viral and non-viral gene therapy using 3D (bio)printing.

The overall success in launching discovered drugs is tightly restricted to the high rate of late-stage failures, which ultimately inhibits the distribution of medicines in markets. As a result, it is imperative that methods reliably predict the effectiveness and, more critically, the toxicity of medicine early in the drug development process before clinical trials be continuously innovated. We must stay up to date with the fast appearance of new infections and diseases by rapidly developing the requisite vaccinations and medicines. Modern in vitro models of disease may be used as an alternative to traditional disease models, and advanced technology can be used for the creation of pharmaceuticals as well as cells, drugs, and gene delivery systems to expedite the drug discovery procedure. Furthermore, in vitro models that mimic the spatial and chemical characteristics of native tissues, such as a 3D bioprinting system or other technologies, have proven to be more effective for drug screening than traditional 2D models. Viral and non-viral gene delivery vectors are a hopeful tool for combinatorial gene therapy, suggesting a quick way of simultaneously deliver multiple genes. A 3D bioprinting system embraces an excellent potential for gene delivery into the different cells or tissues for different diseases, in tissue engineering and regeneration medicine, in which the precise nucleic acid is located in the 3D printed tissues and scaffolds. Non-viral nanocarriers, in combination with 3D printed scaffolds, are applied to their delivery of genes and controlled release properties. There remains, however, a big obstacle in reaching the full potential of 3D models because of a lack of in vitro manufacturing of live tissues. Bioprinting advancements have made it possible to create biomimetic constructions that may be used in various drug discovery research applications. 3D bioprinting also benefits vaccinations, medicines, and relevant delivery methods because of its flexibility and adaptability. This review discusses the potential of 3D bioprinting technologies for pharmaceutical studies.

Prevascularized Micro-/Nano-Sized Spheroid/Bead Aggregates for Vascular Tissue Engineering.

Efficient strategies to promote microvascularization in vascular tissue engineering, a central priority in regenerative medicine, are still scarce; nano- and micro-sized aggregates and spheres or beads harboring primitive microvascular beds are promising methods in vascular tissue engineering. Capillaries are the smallest type and in numerous blood vessels, which are distributed densely in cardiovascular system. To mimic this microvascular network, specific cell components and proangiogenic factors are required. Herein, advanced biofabrication methods in microvascular engineering, including extrusion-based and droplet-based bioprinting, Kenzan, and biogripper approaches, are deliberated with emphasis on the newest works in prevascular nano- and micro-sized aggregates and microspheres/microbeads.

Emerging Phospholipid Nanobiomaterials for Biomedical Applications to Lab-on-a-Chip, Drug Delivery, and Cellular Engineering.

The design of advanced nanobiomaterials to improve analytical accuracy and therapeutic efficacy has become an important prerequisite for the development of innovative nanomedicines. Recently, phospholipid nanobiomaterials including 2-methacryloyloxyethyl phosphorylcholine (MPC) have attracted great attention with remarkable characteristics such as resistance to nonspecific protein adsorption and cell adhesion for various biomedical applications. Despite many recent reports, there is a lack of comprehensive review on the phospholipid nanobiomaterials from synthesis to diagnostic and therapeutic applications. Here, we review the synthesis and characterization of phospholipid nanobiomaterials focusing on MPC polymers and highlight their attractive potentials for applications in micro/nanofabricated fluidic devices, biosensors, lab-on-a-chip, drug delivery systems (DDSs), COVID-19 potential usages for early diagnosis and even treatment, and artificial extracellular matrix scaffolds for cellular engineering.

Roles of E6 and E7 Human Papillomavirus Proteins in Molecular Pathogenesis of Cervical Cancer.

Human papillomavirus (HPV) cancers are expected to be major global health concerns in the upcoming decades. The growth of HPV-positive cancer cells depends on the consistent expression of oncoprotein which has been poorly taken into account in the cellular communication. Among them, E6/E7 oncoproteins are attractive therapeutic targets as their inhibition rapidly leads to the onset of aging in HPV-positive cancer cells. This cellular response is associated with the regeneration of p53, pRb anti-proliferative proteins as well as the mTOR signaling pathway; hence, the identification of involved and application of E6/E7 inhibitors can lead to new therapeutic strategies. In the present review, we focused on the pathogenicity of E6/E7 Proteins of human papillomavirus and their roles associated with the cervical cancer.

MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease with autosomal recessive inheritance pattern often seen around the Mediterranean Sea. It is characterized by recurrent episodes of fever and polyserositis and rash. Recently, MEFV gene analysis determines the definitive diagnosis of FMF. In this study, we analyzed 12 MEFV gene mutations in more than 200 FMF patients, previously diagnosed by Tel-Hashomer clinical criteria, in northwest of Iran, located in the proximity of the Mediterranean Sea. In the northwest of Iran (Ardabil), 216 patients with FMF diagnosis, based on Tel-Hashomer criteria, referred to the genetic laboratory to be tested for the following mutations; P369S, F479L, M680I(G/C), M680I(G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H, E148Q. All patients were screened for MEFV gene mutations by a reverse hybridization assay (FMF Strip Assay, Vienna lab, Vienna, Austria) according to manufacturer's instructions. Among these FMF patients, no mutation was detected in 51 (23/62%) patients, but 165 (76/38%) patients had one or two mutations, 33 patients (15/28%) homozygous, 86 patients (39/81%) compound heterozygous and 46 patients (21/29%) were heterozygous. The most common mutations were M694V (23/61%), V726A (11/11%) and E148Q (9/95%) respectively. MEFV gene mutations showed similarities and dissimilarities in different ethnic groups, while it is common among Arabs and Armenians genotype. Since common 12 MEFV gene analysis could not detect up to 50% of our patients, who had FMF on the basis of clinical Tel-Hashomer criteria, clinical criteria is still the best way in the diagnosis of FMF in this area. The abstract of this article has been presented in the 7th Congress of International Society of Systemic Auto-Inflammatory Diseases in Lausanne, Switzerland, 22-26 May 2013.

IVIG Effects on Erythrocyte Sedimentation Rate in Children.

Background. Erythrocyte sedimentation rate (ESR) is a valuable laboratory tool in evaluation of infectious, inflammatory, and malignant diseases. Red blood cells in outside from the body precipitate due to their higher density than the plasma. In this study we discuss the IVIG effect on ESR in different diseases and different ages. Methods and Materials. Fifty patients under 12 years old who had indication to receive IVIG enrolled in this study. Total dose of IVIG was 2 gr/kg (400 mg/kg in five days or 2 gr/kg in single dose). ESR before infusion of IVIG and within 24 hours after administration of the last dose of IVIG was checked. Results. 23 (46%) patients were males and 27 (54%) were females. The mean of ESR before IVIG was 31.8 ± 29.04 and after IVIG it was 47.2 ± 36.9; this difference was meaningful (P = 0.05). Results of ESR changes in different age groups, 6 patients less than 28 days, 13 patients from 1 month to 1 year, 20 patients from 1 to 6 years old, and 11 patients from 6 to 12 years have been meaningful (P = 0.001, P = 0.025, and P = 0.006, resp.). Conclusion. In patients who are receiving IVIG as a therapy, ESR increased falsely (noninflammatory rising); therefore use of ESR for monitoring of response to treatment may be unreliable. Although these results do not apply to neonatal group, we suggest that, in patients who received IVIG, interpretation of ESR should be used cautiously on followup.

PFAPA and 12 Common MEFV Gene Mutations Our Clinical Experience.

OBJECTIVE: Marshall Syndrome or PFAPA is an inflammatory periodic disease characterized by periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Although PFAPA is an auto inflammatory disease, it doesn't have genetic basis such as other periodic fevers. This study evaluates the 12 common MEFV gene mutations in patients with PFAPA syndrome. METHODS: 21 patients with PFAPA syndrome who had diagnostic criteria were enrolled in this study and 12 common MEFV gene mutations i.e. P369S, F479L, M680I (G/C), M680I (G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H, E148Q evaluated. All the patients were screened for MEFV gene mutations by a reverse hybridization assay (FMF Strip Assay, Vienna lab, Vienna, Austria) according to the instructions provided by the manufacturer. Findings : The age of patients was between 6 months to 14 years, and 15 were males. Seven patients had heterozygote and one had compound heterozygote (K695R, V725A) mutation. There were 4 alleles M694V, 3 alleles V726A, 1 allele E148Q and 1 allele K694R. No significant difference existed between mutated patients with non-mutated in symptoms like aphthous and stomatitis, duration of attacks, episodes of fever and response to treatment. Gaslini score test was not helpful to predict the probability of gene mutations. CONCLUSION: About 30 percent of patients had MEFV gene mutations but these mutations did not play a main role in presentation of PFAPA symptoms.

Dapsone as an alternative therapy in children with familial mediterranean Fever.

OBJECTIVE: Familial Mediterranan Fever is an hereditary autoinflammatory disease that presents with recurrent febrile attacks and poly serositis. Colchicine is the only known treatment in this diease. However, nearly 5-10% of patients are resistant to colchicines. There are many different modalities in colchicine resistant patients, biologic and immunosupressive drugs being the known ones. We studied the efficacy of Dapsone as an anti inflammatory drug in children with FMF who did not tolerate colchicine well. METHODS: This is a case series study in 10 patients who had FMF on the base of Tel-Hashomer criteria and did not tolerate colchicine or did not respond to it well. Patients took 2mg/kg dapsone in single dose, during 6 months. FINDINGS: In four patients episodic attacks returned after 27 days, so the drug was discontinued. One patient refused to continue the study; in five patients dapsone was taken in average for 8 months and 6 days, at least for 6 months. These five patients had no episodes of attack during the following observation. CONCLUSION: Dapsone could control episodic attacks of FMF in 50% of cases. It might be considered as an alternative therapy in FMF cases not responding to colchicine.