IL-12/IL23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis causing chronic and recalcitrant painful ulcerations. Pathogenic mechanisms are yet poorly understood limiting therapeutic options, however, IL-12/IL-23 inhibition via ustekinumab has previously been associated with positive outcomes. We aimed to elucidate the dysregulated immune landscape of PG and lesional skin changes associated with IL-12/IL-23 blockade. We applied spatial transcriptomics and comparative computation analysis on lesional biopsies from two patients obtained before and after IL-12/IL-23 blockade with ustekinumab. Our data indicate lesional PG skin exhibits complex patterns of inflammation, including a not previously described major infiltration of B cells and establishment of tertiary lymphoid structures. In both patients, IL-12/IL-23 blockade led to marked clinical improvement but was associated with amelioration of contrasting inflammatory pathways. Notably, plasma cell markers and tertiary structures were recalcitrant to the treatment regime suggesting that B cells might play a role in the refractory nature of PG.

Tertiary lymphoid structures sustain cutaneous B cell activity in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic skin condition affecting approximately 1% of the US population. HS skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu, the biology and the contribution of these cells in HS pathogenesis are unclear. We aimed to investigate the dynamics and microenvironmental interactions of B cells within cutaneous HS lesions. Combining histological analysis, single-cell RNA sequencing, and spatial transcriptomics profiling of HS lesions, we defined the tissue microenvironment relative to B cell activity within this disease. Our findings identified tertiary lymphoid structures (TLSs) within HS lesions and described organized interactions among T cells, B cells, antigen-presenting cells, and skin stroma. We found evidence that B cells within HS TLSs actively underwent maturation, including participation in germinal center reactions and class switch recombination. Moreover, skin stroma and accumulating T cells were primed to support the formation of TLSs and facilitate B cell recruitment during HS. Our data definitively demonstrated the presence of TLSs in lesional HS skin and point to ongoing cutaneous B cell maturation through class switch recombination and affinity maturation during disease progression in this inflamed nonlymphoid tissue.

Current Clinical Trial Landscape of OX40 Agonists.

PURPOSE OF REVIEW: Despite the efficacy of immune checkpoint blockade (ICB) immunotherapy, most cancer patients still develop progressive disease necessitating additional treatment options. One approach is ligation of the OX40 (CD134) costimulatory receptor which promotes T cell activation, effector function, and the generation of long-lived memory cells. RECENT FINDINGS: Numerous preclinical studies have demonstrated that OX40 agonists alone or in combination with ICB (e.g., anti-PD-1, anti-PD-L1, and anti-CTLA-4) augment anti-tumor immunity. In this review, we discuss the impact of OX40 agonists on T cell function and the therapeutic potential of OX40 agonists alone or in conjunction with ICB for patients with advanced malignancies.

Mixed Bacteriophage MS2-L2 VLPs Elicit Long-Lasting Protective Antibodies against HPV Pseudovirus 51.

Three prophylactic vaccines are approved to protect against HPV infections. These vaccines are highly immunogenic. The most recent HPV vaccine, Gardasil-9, protects against HPV types associated with ~90% of cervical cancer (worldwide). Thus, ~10% of HPV-associated cancers are not protected by Gardasil-9. Although this is not a large percentage overall, the HPV types associated with 10% of cervical cancer not protected by the current vaccine are significantly important, especially in HIV/AIDS patients who are infected with multiple HPV types. To broaden the spectrum of protection against HPV infections, we developed mixed MS2-L2 VLPs (MS2-31L2/16L2 VLPs and MS2-consL2 (69-86) VLPs) in a previous study. Immunization with the VLPs neutralized/protected mice against infection with eleven high-risk HPV types associated with ~95% of cervical cancer and against one low-risk HPV type associated with ~36% of genital warts & up to 32% of recurrent respiratory papillomatosis. Here, we report that the mixed MS2-L2 VLPs can protect mice from three additional HPV types: HPV51, which is associated with ~0.8% of cervical cancer; HPV6, which is associated with up to 60% of genital warts; HPV5, which is associated with skin cancers in patients with epidermodysplasia verruciformis (EV). Overall, mixed MS2-L2 VLPs can protect against twelve HPV types associated with ~95.8% of cervical cancers and against two HPV types associated with ~90% of genital warts and >90% recurrent respiratory papillomatosis. Additionally, the VLPs protect against one of two HPV types associated with ~90% of HPV-associated skin cancers in patients with EV. More importantly, we observed that mixed MS2-L2 VLPs elicit protective antibodies that last over 9 months. Furthermore, a spray-freeze-dried formulation of the VLPs is stable, immunogenic, and protective at room temperature and 37 °C.

From ER to OR-Type A aortic dissection delay dilemma.

BACKGROUND AND AIM OF STUDY: Aortic dissection (AD) remains a life-threatening and time-critical condition. The classical presentation involves sudden onset, sharp "tearing" chest pain radiating to the back. However, it can present with a myriad of symptoms, leading to a high occurrence of misdiagnosis and delay in treatment. METHODS AND RESULTS: A review of the available literature published on AD and diagnostic delays. A systematic review of the literature performed via PubMed and Google scholar using key search terms such as "type A," "aortic dissection," "delay," "misdiagnosis," and synonyms. The Boolean operator used to narrow results specifically to diagnostic elements of AD. A current lack of data collection has impeded the systematic analysis and review of this condition making it difficult to assess reasons for delay. A review of the literature showed a large variation in the presentation of those that have acute AD. Often the presentation mimics other more common conditions such as acute coronary syndrome. Lack of awareness amongst clinicians means that it is often not considered as a differential. Furthermore, the lack of a discriminator for patients being triaged leads to diagnostic delay; this is exacerbated by limited accessibility to diagnostic tests such as CT. CONCLUSION: Based on the current literature, collaborative data collection, regular audit, national guidance, and communication between Royal Colleges will improve awareness, reduce diagnostic delays, and shine greater light on the issue.

Virus-like Particle-Based L2 Vaccines against HPVs: Where Are We Today?

Human papillomaviruses (HPVs) are the most common sexually transmitted infections worldwide. Ninety percent of infected individuals clear the infection within two years; however, in the remaining 10% of infected individuals, the infection(s) persists and ultimately leads to cancers (anogenital cancers and head and neck cancers) and genital warts. Fortunately, three prophylactic vaccines have been approved to protect against HPV infections. The most recent HPV vaccine, Gardasil-9 (a nonavalent vaccine), protects against seven HPV types associated with ~90% of cervical cancer and against two HPV types associated with ~90% genital warts with little cross-protection against non-vaccine HPV types. The current vaccines are based on virus-like particles (VLPs) derived from the major capsid protein, L1. The L1 protein is not conserved among HPV types. The minor capsid protein, L2, on the other hand, is highly conserved among HPV types and has been an alternative target antigen, for over two decades, to develop a broadly protective HPV vaccine. The L2 protein, unlike the L1, cannot form VLPs and as such, it is less immunogenic. This review summarizes current studies aimed at developing HPV L2 vaccines by multivalently displaying L2 peptides on VLPs derived from bacteriophages and eukaryotic viruses. Recent data show that a monovalent HPV L1 VLP as well as bivalent MS2 VLPs displaying HPV L2 peptides (representing amino acids 17-36 and/or consensus amino acids 69-86) elicit robust broadly protective antibodies against diverse HPV types (6/11/16/18/26/31/33/34/35/39/43/44/45/51/52/53/56/58/59/66/68/73) associated with cancers and genital warts. Thus, VLP-based L2 vaccines look promising and may be favorable, in the near future, over current L1-based HPV vaccines and should be explored further.

Oral immunization with bacteriophage MS2-L2 VLPs protects against oral and genital infection with multiple HPV types associated with head & neck cancers and cervical cancer.

Human papillomaviruses (HPVs) are the most common sexually transmitted infections. HPVs are transmitted through anogenital sex or oral sex. Anogenital transmission/infection is associated with anogenital cancers and genital warts while oral transmission/infection is associated with head and neck cancers (HNCs) including recurrent respiratory papillomatosis. Current HPV vaccines protect against HPV types associated with ∼90% of cervical cancers and are expected to protect against a percentage of HNCs. However, only a few studies have assessed the efficacy of current vaccines against oral HPV infections. We had previously developed a mixed MS2-L2 candidate HPV vaccine based on bacteriophage MS2 virus-like particles (VLPs). The mixed MS2-L2 VLPs consisted of a mixture of two MS2-L2 VLPs displaying: i) a concatemer of L2 peptide (epitope 20-31) from HPV31 & L2 peptide (epitope 17-31) from HPV16 and ii) a consensus L2 peptide representing epitope 69-86. The mixed MS2-L2 VLPs neutralized/protected mice against six HPV types associated with ∼87% of cervical cancer. Here, we show that the mixed MS2-L2 VLPs can protect mice against additional HPV types; at the genital region, the VLPs protect against HPV53, 56, 11 and at the oral region, the VLPs protect against HPV16, 35, 39, 52, and 58. Thus, mixed MS2-L2 VLPs protect against eleven oncogenic HPV types associated with ∼95% of cervical cancer. The VLPs also have the potential to protect, orally, against the same oncogenic HPVs, associated with ∼99% of HNCs, including HPV11, which is associated with up to 32% of recurrent respiratory papillomatosis. Moreover, mixed MS2-L2 VLPs are thermostable at room temperature for up to 60 days after spray-freeze drying and they are protective against oral HPV infection.

Epidemiology, Microbiology and Antibiotic Sensitivity of Odontogenic Space Infections in Central India.

INTRODUCTION: Odontogenic infections are the most commonly encountered orofacial infections, which may spread into the adjacent anatomical spaces along the contiguous fascial planes, leading to involvement of multiple spaces which can progress to life-threatening situations. MATERIALS AND METHODS: A prospective study was carried out on 100 consecutive cases of odontogenic infections treated at our institute over a period of 18 months by surgical intervention and intravenous antibiotics. Morphologic study of the isolates and antibiotic sensitivity testing was performed. RESULTS: Caries was the most frequent dental disease (53.27%), and the mandibular first molar was the most frequently involved tooth (41.9%) associated with the etiology of odontogenic infections. A total of 158 spaces were involved in 100 patients. In subjects with single space odontogenic infections (n = 61), submandibular space was most commonly affected (44.26%) followed by buccal space (27%). In subjects with multiple space infections (n = 39), submandibular space (30.19%) was most frequently involved followed by buccal space (17.92%). In the aerobic group/microaerophilic group, 17 different species were isolated in a total of 102 aerobic isolates. A total of 18 species were identified in 65 anaerobic isolates sampled. CONCLUSION: Amoxicillin possess antimicrobial activity against major pathogens in orofacial odontogenic infections, but ß-lactamase production has restricted the effectiveness of amoxicillin against the resistant strains of Staphylococcus aureus, Bacteroides, Prevotella and Porphyromonas. For the management of orofacial infections, the use of amoxicillin/clavulanate and clindamycin is recommended because of stability against ß-lactamases.