HBV-HCC treatment with mRNA electroporated HBV-TCR T cells

Hepatocellular carcinoma is a significant global health challenge with steadily increasing incidence in the East Asia region. While both Hepatitis C and B virus infections account for the majority of HCC cases, the advent of potent antivirals against HCV infection have biased the aetiology towards chronic HBV infection that at the moment remains without an effective cure. For this reason, HBV-HCC remains a persistent global problem. Treatment options for intermediate to advance stages of HBV-HCC remains limited, hence novel therapeutic strategies are required to fulfil this medical need. Following the considerable success of adoptive T cell immunotherapy against B cell malignancies, it is conceivable to envision whether the same could be achieved against HBV-HCC. In this review, we describe the development of T cell therapy strategies for HBV-HCC and discuss the safety and the efficacy of the strategy in terms of the direct killing of tumour cells and the other alterations possibly induced by the action of the T cells.

Marine Invertebrate Peptides: Antimicrobial Peptides

Antimicrobial peptides are an important component of many organisms’ innate immune system, with a good inhibitory or killing effect against the invading pathogens. As a type of biological polypeptide with natural immune activities, antimicrobial peptides have a broad spectrum of antibacterial, antiviral, and antitumor activities. Nevertheless, these peptides cause no harm to the organisms themselves. Compared with traditional antibiotics, antimicrobial peptides have the advantage of not producing drug resistance and have a unique antibacterial mechanism, which has attracted widespread attention. In this study, marine invertebrates were classified into arthropods, annelids, mollusks, cnidarians, and tunicata. We then analyzed the types, sources and antimicrobial activities of the antimicrobial peptides in each group. We also reviewed the immune mechanism from three aspects: membrane-targeted direct killing effects, non-membrane targeting effects and immunomodulatory effects. Finally, we discussed their applications and the existing problems facing antimicrobial peptides in actual production. The results are expected to provide theoretical support for future research and applications of antimicrobial peptides in marine invertebrates.

Vitamin C, From Supplement to Treatment: A Re-Emerging Adjunct for Cancer Immunotherapy?

Vitamin C (VitC), in addition to its role as a general antioxidant, has long been considered to possess direct anti-cancer activity at high doses. VitC acts through oxidant and epigenetic mechanisms, which at high doses can exert direct killing of tumor cells in vitro and delay tumor growth in vivo. Recently, it has also been shown that pharmacologic-dose VitC can contribute to control of tumors by modulating the immune system, and studies have been done interrogating the role of physiologic-dose VitC on novel adoptive cellular therapies (ACTs). In this review, we discuss the effects of VitC on anti-tumor immune cells, as well as the mechanisms underlying those effects. We address important unanswered questions concerning both VitC and ACTs, and outline challenges and opportunities facing the use of VitC in the clinical setting as an adjunct to immune-based anti-cancer therapies.

Persister cells: formation, resuscitation and combative therapies

Persister cells, or superfits, have been strongly implicated in the recalcitrance and recurrence of chronic bacterial infection through the dormant (metabolically reduced) phenotype they display and the tolerance to antimicrobial agents this dormancy grants them. The complex biochemical events that lead to the formation of persister cells are not completely understood, though much research has linked the degradation of type II toxin/antitoxin systems and reduced cellular ATP levels to the rise in stress response molecules (where (p)ppGpp is of particular interest), which induce this dormant state. The equally complex mechanism of resuscitation is initiated by the cells’ ability to sense nutrient availability via chemotaxis systems. Levels of secondary messenger proteins (i.e., cAMP) within the cell are reduced to allow the resuscitation of ribosomes, by ribosomal resuscitation factor HflX, to reinstate protein synthesis and, therefore, growth to re-populate. Techniques of superfit eradication utilise one, or more, of three approaches (i) direct killing, (ii) re-sensitising persister cells to conventional antimicrobials, or (iii) prevention of persister formation though few laboratory findings have been translated to clinical practice. This work will outline current findings in the field with a critical approach, where possible.

Host Defense Peptides: Dual Antimicrobial and Immunomodulatory Action

The rapid rise of multidrug-resistant (MDR) bacteria has once again caused bacterial infections to become a global health concern. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), offer a viable solution to these pathogens due to their diverse mechanisms of actions, which include direct killing as well as immunomodulatory properties (e.g., anti-inflammatory activity). HDPs may hence provide a more robust treatment of bacterial infections. In this review, the advent of and the mechanisms that lead to antibiotic resistance will be described. HDP mechanisms of antibacterial and immunomodulatory action will be presented, with specific examples of how the HDP aurein 2.2 and a few of its derivatives, namely peptide 73 and cG4L73, function. Finally, resistance that may arise from a broader use of HDPs in a clinical setting and methods to improve biocompatibility will be briefly discussed.

Study of Antifungal Activity Using Three Chinese Medicine Herbs

Chinese medicine herbal extracts are ideal candidates to replace toxic industrial wood preservatives thanks to their antifungal and nontoxic properties. To investigate the antifungal activity of Chinese herbal medicines, in this study, Trametes versicolor fungi were selected as test strains to evaluate the antifungal properties of Fructus Cnidii, Fructus Forsythiae, and Radix Stemonae. The results show that Fructus Cnidii has a strong inhibitory effect against T. versicolor, whereas Fructus Forsythiae and Radix Stemonae have a weak inhibitory effect. The hyphae growth cycle shows that the three studied Chinese herbs disrupt the growth of T. versicolor. Moreover, instead of direct killing, the Chinese herbal medicine demonstrated inhibition ability. Furthermore, the morphological and toxicological evidence shows that Fructus Cnidii affected the expression of proteins or enzymes to achieve the inhibition goal. In sum, this study could provide both primary data and a theoretical foundation for further developing and applying for traditional Chinese medicine as a green type of wood preservative.

Carbon and nitrogen isotope evidence for widespread presence of anoxic intermediate waters before and during the Permian-Triassic mass extinction

The largest mass extinction since the advent of animals occurred during the Permian-Triassic (P-Tr) transition, ca. 252 Ma, and is commonly attributed to the eruption of the Siberian Traps large igneous province. However, the direct killing mechanism is still debated. In this study, we investigated marine redox conditions of the intermediate water column that most organisms inhabit with special attention to the time interval before the onset of the mass extinction. The carbon isotope composition of carbonate and organic carbon (δ13Ccarb and δ13Corg) as well as the nitrogen isotope composition of bulk nitrogen (δ15N) were analyzed in four P-Tr boundary sequences (Zhongli, Jianshi, Ganxi, and Chaotian sections), which record a transect from a shallow water carbonate platform to a deep water, lower ramp slope in South China. δ13Ccarb shows a distinct negative shift in all sections and displays a clear, 2−4‰, decreasing gradient accompanying an increase in water depth both before and after the mass extinction. A distinct negative shift in δ15N is observed in the shallow water Zhongli section, whereas a minor negative shift is present in the three deeper water sections. Before the mass extinction, the δ15N values from shallow water sections are higher than those from deeper waters. The low δ15N values close to 0‰ in deeper water sections suggest that microbial nitrogen fixation was the predominant source of biologically available nitrogen before the onset of the mass extinction. Thus, the water depth- dependent gradient in δ13Ccarb and δ15N suggests that an oxygen-deficient intermediate water column was already present before the mass extinction. The uniform δ15N values around 0‰ accompanying the onset of the mass extinction reveal that anoxic intermediate waters expanded into shallow waters. Meanwhile, the distinct positive shift in δ13Corg observed in upper ramp slope sections, i.e., the Jianshi and Ganxi sections, suggests that a euxinic photic zone was at least episodically present in the earliest Triassic. The temporal coincidence between the expansion of intermediate water column anoxia and the onset of the P-Tr mass extinction supports the hypothesis that marine anoxia was a direct killing mechanism.

Oncolytic Herpes Simplex Virus-Based Therapies for Cancer

With the increased worldwide burden of cancer, including aggressive and resistant cancers, oncolytic virotherapy has emerged as a viable therapeutic option. Oncolytic herpes simplex virus (oHSV) can be genetically engineered to target cancer cells while sparing normal cells. This leads to the direct killing of cancer cells and the activation of the host immunity to recognize and attack the tumor. Different variants of oHSV have been developed to optimize its antitumor effects. In this review, we discuss the development of oHSV, its antitumor mechanism of action and the clinical trials that have employed oHSV variants to treat different types of tumor.

Risk-Induced Trait Responses and Non-consumptive Effects in Plants and Animals in Response to Their Invertebrate Herbivore and Parasite Natural Enemies

Predators kill and consume prey, but also scare living prey. Fitness of prey can be reduced by direct killing and consumption, but also by non-consumptive effects (NCEs) if prey show costly risk-induced trait responses (RITRs) to predators, which are meant to reduce predation risk. Recently, similarities between predators and parasites as natural enemies have been recognized, including their potential to cause victim RITRs and NCEs. However, plant-herbivore and animal host-parasite associations might be more comparable as victim-enemy systems in this context than either is to prey-predator systems. This is because plant herbivores and animal parasites are often invertebrate species that are typically smaller than their victims, generally cause lower lethality, and allow for further defensive responses by victims after consumption begins. Invertebrate herbivores can cause diverse RITRs in plants through various means, and animals also exhibit assorted RITRs to increased parasitism risk. This synthesis aims to broadly compare these two enemy-victim systems by highlighting the ways in which plants and animals perceive threat and respond with a range of induced victim trait responses that can provide pre-emptive defense against invertebrate enemies. We also review evidence that RITRs are costly in terms of reducing victim fitness or abundance, demonstrating how work with one victim-enemy system can inform the other with respect to the frequency and magnitude of RITRs and possible NCEs. We particularly highlight gaps in our knowledge about plant and animal host responses to their invertebrate enemies that may guide directions for future research. Comparing how potential plant and animal victims respond pre-emptively to the threat of consumption via RITRs will help to advance our understanding of natural enemy ecology and may have utility for pest and disease control.