Radiotherapy as an immune checkpoint blockade combination strategy for hepatocellular carcinoma

In the immune oncology era,the clinical efficacy of immune checkpoint inhibitors(ICIs)against most solid cancers is well known.In hepatocellular carcinoma,the recent success of combination therapy with targeting agents has accelerated the search for novel combination strategies.Radiotherapy(RT),an attractive modality,can be combined with ICIs,which act as strong modulators of the tumor immune microenvironment.Herein,we discuss immune modulation caused by radiation and the current trials of RT-ICI combination treatment as well as future perspectives.

Tweaking the immune system as an adjuvant for the treatment of retinal degenerations

Blinding diseases such as photoreceptor degenerations are debilitating conditions that severely impair daily lives of affected patients.This group of diseases are amenable to photoreceptor replacement therapies and recent transplantation studies provided proof-of-principle for functional recovery at the retinal and behavioral level,though the actual mechanism of repair still needs further investigations.The immune system responds in several ways upon photoreceptor engraftment,resulting in T-cell and macrophage infiltrations and,consequently,decrease in graft survival.Most studies on the role of the immune system suggest a detrimental effect in a therapeutic setting.Conversely,the opposite idea wherein the immune system can be activated towards a protective state was also explored in other experimental paradigms.Here,Neves and colleagues explored the potential of cross-species studies and,to a certain extent,the concept of a protective immune system in retinal degeneration and therapy.Mesencephalic astrocyte-derived neurotrophic factor(MANF)was identified in this study as a novel factor that,by modulating the immune system,can slow down photoreceptor degeneration and improve transplantation outcome.

Viruses and autism: A Bi-mutual cause and effect

Autism spectrum disorder(ASD)is a group of heterogeneous,multi-factorial,neurodevelopmental disorders resulting from genetic and environmental factors interplay.Infection is a significant trigger of autism,especially during the critical developmental period.There is a strong interplay between the viral infection as a trigger and a result of ASD.We aim to highlight the mutual relationship between autism and viruses.We performed a thorough literature review and included 158 research in this review.Most of the literature agreed on the possible effects of the viral infection during the critical period of development on the risk of developing autism,especially for specific viral infections such as Rubella,Cytomegalovirus,Herpes Simplex virus,Varicella Zoster Virus,Influenza virus,Zika virus,and severe acute respiratory syndrome coronavirus 2.Viral infection directly infects the brain,triggers immune activation,induces epigenetic changes,and raises the risks of having a child with autism.At the same time,there is some evidence of increased risk of infection,including viral infections in children with autism,due to lots of factors.There is an increased risk of developing autism with a specific viral infection during the early developmental period and an increased risk of viral infections in children with autism.In addition,children with autism are at increased risk of infection,including viruses.Every effort should be made to prevent maternal and early-life infections and reduce the risk of autism.Immune modulation of children with autism should be considered to reduce the risk of infection.

Antifatigue,Antioxidant and Immunoregulatory Effects of Peptides Hydrolyzed from Manchurian Walnut(Juglans mandshurica Maxim.) on Mice

The Manchurian walnut(Juglans mandshurica Maxim.) is rich in proteins, whereas this resource has not been used efficiently. The antifatigue, antioxidative and immunoregulatory effects of Manchurian walnut hydrolysate peptides(MWHPs)were evaluated in this study. MWHPs with a degree of hydrolysis of 32.23% were ultrafiltered and divided into three fractions,namely, high(> 10 k Da), medium(3–10 kDa), and low molecular weight(< 3 kDa), and then fed to mice continuously at doses of 200, 400 or 800 mg/(kg·d). The antifatigue, antioxidative, and immunoregulatory effects of the peptides were tested on the second and fourth weeks of MWHP administration. Results showed that low-molecular-weight MWHPs exerted significant antifatigue(prolonging swimming time, elevating liver glycogen contents, and reducing lactic acid contents), antioxidative(enhancing superoxide dismutase(SOD), GSH-Px, and catalase(CAT) activities and reducing malondialdehyde(MDA) content), and immunoregulatory(raising the immune-organ index and promoting T-lymphocyte proliferation and s Ig A secretion in the intestinal tract) effects. This research indicates that MWHPs have potential applications in health care and may be developed as a base for new functional foods.

Role of β-microseminoprotein from prostate cancer initiationto recurrence: A mini-review

Medline/Pubmed articles relevant to this topic were considered using the search terms ?-microseminoprotein, MSMB, prostate secretory protein of 94 amino acids and PSP94. Full articles were retrieved when the abstract was considered relevant. In addition, other data related to this topic including our own are discussed. Summary of fi ndings-?-microseminoprotein(MSMB) is increasingly being considered as a marker for prostatecancer, as reduced levels have been associated with the disease. Here we review various aspects of this protein including its biological and physiological variants, binding proteins and immune modulation; its importance as a marker for biochemical recurrence of prostate cancer; prostate cancer related splice variants and its therapeutic utility. Two of the most important properties of MSMB are related to anticancer functions and immune modulation. Predominant expression of two(short and full-length) splice variants of MSMB has been observed from normal prostate and several other tissues. In benign prostate hyperplasia the short isoform is dominant, constituting 98% of this isoform, whereas in prostate cancer 96% constitute the fulllength isoform. The MSMB promoter single nucleotide polymorphism rs10993994 with the C allele functions as an activated cyclic adenosine monophosphate response element binding protein binding site. This C variant of rs10993994 could be responsible for the production of splice variants under variable conditions. MSMB has binding motifs to a few known proteins including immunoglobulin G and several Cysteine-rich secretory proteins family proteins. MSMB bound to these proteins is considered as immune modulating. Use of MSMB as a urinary marker for detecting aggressive prostate cancers that could resist radiation and surgical treatments, seems possible, but needs further investigation. The ratio of MSMB splice variants could also be a possible approach in understanding prostate cancers, with higher ratios indicating severe disease.

Historical evolution,overview,and therapeutic manipulation of costimulatory molecules

Co-stimulatory molecules are key mediators in the regulation of immune responses and knowledge of its different families,structure,and functions has improved in recent decades.Understanding the role of co-stimulatory molecules in pathological processes has allowed the development of strategies to modulate cellular functions.Currently,modulation of co-stimulatory and co-inhibitory molecules has been applied in clinical applications as therapeutic targets in diseases and promising results have been achieved.

Treatment of Multiple Sclerosis

Background: A new method of immune-based therapies has been made and applied on multiple sclerosis patients in last decades. Some of these treatments have a high efficacy and reasonable side effects. In slowing disease progression, present treatments have significant limitations, but often associated with significant adverse effects of immunosuppression, with having a bit low capability to counter the disability. Methods: This is a review meta-analysis of treatment of multiple sclerosis. Results: Thus a valuable aim for multiple sclerosis clinical research is to introduce more effective therapies. Conclusion: It is absolutely necessary to increase the individualized therapy planes development in respect to make better planes to disease-modifying treatments.

Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum

Colostrum provides essential nutrients and immunologically active factors that are beneficial to newborns.Our previous work demonstrated that milk contains large amounts of miRNA that is largely stored in milk-derived microvesicles(MVs).In the present study,we found that the MVs from colostrum contain signifi cantly higher levels of several immune-related miRNAs.We hypothesized that the colostrum MVs may transfer the immune-related miR-NAs into cells,which contribute to its immune modulatory feature.We isolated colostrum MVs by ultracentrifugation and demonstrated several immune modulation features associated with miRNAs.We also provide evidence that the physical structure of milk-derived MVs is essential for transfer miRNAs and following immune modulation effect.Moreover,we found that colostrum powder-derived MVs also contains higher levels of immune-related miRNAs that display similar immune modulation effects.Taken together,these results show that MV-containing immunerelated miRNAs may be a novel mechanism by which co-lostrum modulates body immune response.

Lobe-specific modulation of B16MET melanoma lung metastases by nephrilin peptide

Aim:Nephrilin peptide modulates systemic immune responses to trauma in contexts characterized by simultaneous inflammation and immunosuppression.This study explores the possibility that nephrilin peptide may modulate lung metastasis,which also occurs in an environment of concurrent inflammation and immunosuppression.Methods:B16MET melanoma cells were injected via the tail vein of mice and the development of lung metastases was recorded in animals treated with nephrilin peptide or vehicle by subcutaneous bolus injection daily for three weeks.In a separate experiment,nephrilin was administered by subcutaneous bolus injection for seven days to study the biodistribution of peptide and possible changes to plasma cytokine levels.Results:Nephrilin significantly suppressed B16MET lung metastases.Suppression was more effective in deep lobes with the poorest access to circulation:accessory>inferior>middle>superior.In a separate biodistribution study in mice,nephrilin showed similar biodistribution levels in kidney,liver,brain,and left lung,but significantly higher accumulation in the lobes of the right lung in a gradient that matched its effectiveness in suppressing metastases(accessory>inferior>middle).The latter environments were also characterized by significantly higher local concentrations of succinate,a proxy for lower levels of oxygenation.Conclusion:Nephrilin accumulates preferentially in the deep lobes of the right lung in mice and inhibits B16MET right lung metastases in a lobe-specific manner.

Tricking the tumour microenvironment into becoming our best rational drug design factory:reversal of immune suppression

The immune cellular components of the tumour microenvironment are a diverse group of cells that paradoxically are now appreciated to have a coordinated opposing duality of either promoting or retarding tumour growth.Manipulating this seemingly dynamic interaction for therapeutic benefit is a hotbed of much research.Recent findings in tumour immunology(both preclinical and clinical)build on more than a century of insights and provide a way forward to improving patient outcomes,long term survival and the predictability of“cures”.This opinion piece attempts to summarise some of these historical and contemporary insights with a view to describing eminently testable therapeutic solutions.

Development of a Functional Assessment of Chronic Illness Therapy item library and primary symptom list for the assessment of patient-reported adverse events associated with immune checkpoint modulators

Aim:To develop a comprehensive item library of patient-reported,immunotherapy-related adverse events(irAEs)that draws from and expands on the Functional Assessment of Chronic Illness Therapy(FACIT)Measurement System.Methods:Literature review and iterative expert input.Based on a literature review of irAEs,we developed a framework of immunotherapy classes and their associated symptoms.Clinical experts then reviewed iterations of symptom summaries and item maps linked to the immunotherapy framework.Experts provided content review and feedback was shared across experts until consensus was reached.The iterative process facilitated creation of a Primary Symptom List associated with immune checkpoint modulators(ICMs),drawn from the larger set of symptoms.Existing FACIT items were mapped to the symptom list,and new items were written as needed to create the item library.Results:The full item library of irAEs is comprised of 239 items,covering 142 unique symptoms across 75 inflammatory reactions/immune conditions.A subset of 66 items comprises a Primary Symptom List considered most common/relevant to ICM treatment.This includes gastrointestinal,skin,pulmonary,neurologic,musculoskeletal,and multiple miscellaneous and constitutional symptoms.Conclusion:The FACIT Immunotherapy Item Library is a compilation of 239 self-report items that capture the wide range of AEs experienced by people receiving immune treatments.A subset of 66 items comprises a Primary Symptom List meant for ICM therapy.Use of items selected from this library is encouraged in clinical research and clinical practice evaluation.

Engineering white blood cell membrane-camouflaged nanocarriers for inflammation-related therapeutics

White blood cells(WBCs)play essential roles against inflammatory disorders,bacterial infections,and cancers.Inspired by nature,WBC membrane-camouflaged nanocarriers(WBC-NCs)have been developed to mimic the“dynamic”functions of WBCs,such as transendothelial migration,adhesion to injured blood vessels,etc,which make them promising for diverse medical applications.WBC-NCs inherit the cell membrane antigens of WBCs,while still exhibiting the robust inflammation-related therapeutic potential of synthetic nanocarriers with excellent(bio)physicochemical performance.This review summarizes the proposed concept of cell membrane engineering,which utilizes physical engineering,chemical modification,and biological functionalization technologies to endow the natural cell membrane with abundant functionalities.In addition,it highlights the recent progress and applications of WBC-NCs for inflammation targeting,biological neutralization,and immune modulation.Finally,the challenges and opportunities in realizing the full potential of WBC-NCs for the manipulation of inflammation-related therapeutics are discussed.

A double-blind,randomized,placebo-and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis

Background:Benvitimod cream,a novel synthetic small molecule,was effective in treating mild-to-moderate plaque psoriasis.We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.Methods:We randomly assigned 686 patients(2:1:1)to receive 1%benvitimod cream,0.005%calcipotriol ointment or placebo twice a day for 12 weeks.The primary efficacy end points were the percentage of patients with a 75%or greater reduction from baseline in the psoriasis area and severity index(PASI 75)score and with a score of 0 or 1 in static physician’s global assessment(sPGA)at week 12.Results:The results showed that 50.4%of patients in the benvitimod group achieved PASI 75,which was significantly higher than that in the calcipotriol(38.5%,P<0.05)and placebo(13.9%,P<0.05)groups.The proportion of patients achieving an sPGA score 0 or 1 was 66.3%in the benvitimod group and 63.9%in the calcipotriol group,which were both significantly higher than that in the placebo group(34%,P<0.05).In the long-term follow-up study,50.8%of patients experienced recurrence.After retreatment with 1%benvitimod,73.3%of patients achieved an sPGA score of 0 or 1 again at week 52.Adverse events included application site irritation,follicular papules,and contact dermatitis.No systemic adverse reactions were reported.Conclusion:During this 12-week study,benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.

Probiotics intervention in colorectal cancer:From traditional approaches to novel strategies

The intestine harbors a large population of microorganisms that interact with epithelial cells to maintain host healthy physiological status.These intestinal microbiota engage in the fermentation of non-digestible nutrients and produce beneficial metabolites to regulate host homeostasis,metabolism,and immune response.The disruption of microbiota,known as dysbiosis,has been implicated in many intestinal diseases,including colorectal cancer(CRC).As the third most common cancer and the second leading cause of cancer-related death worldwide,CRC poses a significant health burden.There is an urgent need for novel interventions to reduce CRC incidence and improve clinical outcomes.Modulating the intestinal microbiota has emerged as a promising approach for CRC prevention and treatment.Current research efforts in CRC probiotics primarily focus on reducing the incidence of CRC,alleviating treatment-related side effects,and potentiating the efficacy of anticancer therapy,which is the key to successful translation to clinical practice.This paper aims to review the traditional probiotics and new interventions,such as next-generation probiotics and postbiotics,in the context of CRC.The underlying mechanisms of probiotic anti-cancer effects are also discussed,including the restoration of microbial composition,reinforcement of gut barrier integrity,induction of cancer cell apoptosis,inactivation of carcinogens,and modulation of host immune response.This paper further evaluates the novel strategy of probiotics as an adjuvant therapy in boosting the efficacy of chemotherapy and immunotherapy.Despite all the promising findings presented in studies,the evaluation of potential risks,optimization of delivery methods,and consideration of intra-patient variability of gut microbial baseline must be thoroughly interpreted before bench-to-bedside translation.

Meningeal lymphatic vasculature,a general target for glioblastoma therapy?

Glioblastoma(GBM)causes nearly universal mortality as a result of the failure of conventional therapies including surgical resection,targeted radiation therapy,and chemotherapy.An increasingly important treatment option is combining immunotherapy with other therapies in both preclinical and clinical studies.The central nervous system(CNS)has been historically considered an immune privileged area,but increasing evidence,including the recent rediscovery of meningeal lymphatic vessels(MLVs),has overturned this notion.MLVs are populated by multiple immune cells and connect the CNS to the periphery by draining cerebrospinal fluid with soluble CNS antigens and immune cells into cervical lymph nodes.In the past few years,more and more studies have indicated that MLVs are involved in the regulation of inflammation and the immune response in the pathogenesis of various CNS diseases including GBM.Here,we explore the critical interlinkages between MLVs and GBM therapies including chemotherapy,radiotherapy and immunotherapy,and propose the meningeal lymphatic vasculature as a general target for GBM therapy.