Exploring the Anticancer Potentials of Polyphenols: A Comprehensive Review of Patents in the Last Five Years.

BACKGROUND: Polyphenols found abundantly in plants exhibit various anti-carcinogenic effects on tumor cells, including angiogenesis, metastasis, anti-proliferating agents, inflammation, and apoptosis. In recent years, many novel polyphenolic compounds with anticancer activity have been identified worldwide, and few of them are promising anticancer drugs to cure or inhibit cancer growth by interfering with cancer initiation, promotion, and progression. OBJECTIVES: This mini-review aims to provide a comprehensive survey of the information about polyphenolic anticancer drugs disclosed in worldwide patents and discuss their possibility of developing as drugs used as anticancer drugs in clinical settings. METHODS: In the present mini-review, we have revealed the anticancer properties of polyphenols presented according to their mechanisms of action. PubMed, Google Patents, and SciDirect databases were used to compile the present study. RESULTS: In the last five years, various anticancer polyphenols were revealed in worldwide patents in the last decades, and their mode of action pointed out cytoskeletal damage, arresting cell cycle, inhibiting kinase, and tumor suppressor protein expression. CONCLUSION: Many newly found polyphenols display a promising anticancer potential both in vitro and in vivo, and a few anticancer polyphenols act to inhibit the growth of various human cancer cells. Also, we have given an overview of patents filed in the last five years related to the anticancer potentials of polyphenols.

Comparative Evaluation of Platelet-Rich Fibrin versus Connective Tissue Grafting in Treatment of Gingival Recession Using Pouch and Tunnel Technique: A Randomized Clinical Study.

Aims: The aim of the study was to compare the clinical efficacy of platelet-rich fibrin (PRF) and connective tissue grafting in the treatment of gingival recession (GR) using pouch and tunnel (P and T) technique. Materials and Methods: A total of 40 Class I or Class II GR defects in 17 patients were randomized treated with P and T with PRF (Group I, n = 20) and P and T with CTG (Group II, n = 20). The parameters measured were plaque index (PI), gingival index (GI), probing pocket depth (PPD), clinical attachment level (CAL), horizontal gingival recession (HGR), vertical gingival recession (VGR), width of attached gingiva (WAG), width of keratinised gingiva (WKG), gingival thickness-mid buccal (GTMB), and gingival thickness interdental papilla (GTIP). Postsurgical discomfort level (PSDL), hypersensitivity score (HS), and patient esthetic score (PES) were recorded using visual analog scale (VAS). The PI, GI, PPD, CAL, HGR, VGR, WAG, WKG, GTMB, and GTIP were assessed at pretreatment (baseline) and 1-, 3-, and 6-month posttreatment. The PSDL, HS, and PES were assessed at baseline, day 10, 1, 3, and 6-month posttreatment. Results: P and T with PRF and CTG resulted in root coverage of 73.75% ± 7.80% and 70.83% ±8.26%, respectively. Patient response and acceptance for the surgical treatment modality showed less discomfort and better esthetics in Group I as compared to Group II. Conclusions: PRF treated sites were comparable to the gold standard CTG with better patient acceptance and a lesser invasive approach in terms of graft procurement.

Spectroscopic, electronic structure, molecular docking, and molecular dynamics simulation study of 7-Trifluoromethyl-1H-indole-2-carboxylic acid as an aromatase inhibitor.

The present work encompasses a combined experimental and theoretical investigation of the molecular structure, vibrational wavenumbers, electronic structure at the ground and electronic excited states, molecular electrostatic potential surface of 7-(Trifluoromethyl)-1H-indole-2-carboxylic acid (TICA) and possibility of the title molecule as an aromatase inhibitor using molecular docking and molecular dynamic simulations. A stable conformer has been obtained using potential energy scans by varying appropriate dihedral angles. The obtained minimum energy conformer was further optimized at the 6-311++G (d, p) basis set by applying the most accepted B3LYP functional. A good agreement between experimental and calculated normal modes of vibration has been observed. The hydrogen-bonded interaction between two monomeric units of TICA has been investigated using NBO,QTAIM, and NCI (noncovalent interactions) analysis. Molecular docking of TICA with human placental aromatase (PDB ID: 3S79) reveals the formation of polar hydrogen bonds as well as hydrophobic interactions between the ligand and the protein, right in the binding cavity. TICA satisfies all pharmacokinetic filters (Lipinski rule of five, the Veber rule, Ghose rule, Egan rule, as well as the Muegge rule) and has a high bioavailability score of 0.85. Dynamic stability of the ligand within the binding pocket of the target protein has been confirmed by 100 ns molecular dynamics simulation results. The present study provides an excellent starting point for additional in vivo research, and TICA may eventually serve as a significant therapeutic candidate for the treatment of breast cancer.

Antiviral CD19+CD27+ Memory B Cells Are Associated with Protection from Recurrent Asymptomatic Ocular Herpesvirus Infection.

Reactivation of herpes simplex virus 1 (HSV-1) from latently infected neurons of the trigeminal ganglia (TG) leads to blinding recurrent herpetic disease in symptomatic (SYMP) individuals. Although the role of T cells in herpes immunity seen in asymptomatic (ASYMP) individuals is heavily explored, the role of B cells is less investigated. In the present study, we evaluated whether B cells are associated with protective immunity against recurrent ocular herpes. The frequencies of circulating HSV-specific memory B cells and of memory follicular helper T cells (CD4+ Tfh cells), which help B cells produce antibodies, were compared between HSV-1-infected SYMP and ASYMP individuals. The levels of IgG/IgA and neutralizing antibodies were compared in SYMP and ASYMP individuals. We found that (i) the ASYMP individuals had increased frequencies of HSV-specific CD19+CD27+ memory B cells, and (ii) high frequencies of HSV-specific switched IgG+CD19+CD27+ memory B cells detected in ASYMP individuals were directly proportional to high frequencies of CD45R0+CXCR5+CD4+ memory Tfh cells. However, no differences were detected in the level of HSV-specific IgG/IgA antibodies in SYMP and ASYMP individuals. Using the UV-B-induced HSV-1 reactivation mouse model, we found increased frequencies of HSV-specific antibody-secreting plasma HSV-1 gD+CD138+ B cells within the TG and circulation of ASYMP mice compared to those of SYMP mice. In contrast, no significant differences in the frequencies of B cells were found in the cornea, spleen, and bone-marrow. Our findings suggest that circulating antibody-producing HSV-specific memory B cells recruited locally to the TG may contribute to protection from symptomatic recurrent ocular herpes. IMPORTANCE Reactivation of herpes simplex virus 1 (HSV-1) from latently infected neurons of the trigeminal ganglia (TG) leads to blinding recurrent herpetic disease in symptomatic (SYMP) individuals. Although the role of T cells in herpes immunity against blinding recurrent herpetic disease is heavily explored, the role of B cells is less investigated. In the present study, we found that in both asymptomatic (ASYMP) individuals and ASYMP mice, there were increased frequencies of HSV-specific memory B cells that were directly proportional to high frequencies of memory Tfh cells. Moreover, following UV-B-induced reactivation, we found increased frequencies of HSV-specific antibody-secreting plasma B cells within the TG and circulation of ASYMP mice compared to those of SYMP mice. Our findings suggest that circulating antibody-producing HSV-specific memory B cells recruited locally to the TG may contribute to protection from recurrent ocular herpes.

Bone Marrow Metastases from Solid Organ Cancer in Adults.

Solid organ cancers infrequently metastasize to bone marrow (BM). BM involvement by cancer in adults leads to poor prognosis and it becomes difficult to provide appropriate treatment. We aimed to study the clinical, pathological and radiological characteristics of adult patients with BM involvement at our institute. Eleven adult patients diagnosed with BM involvement associated with solid organ cancer were included in the study. Clinical, laboratory, radiological and treatment details were analysed. Carcinoma of the breast accounted for majority of the cases. Most of the patients had poor performance status (PS) at diagnosis. Serum lactate dehydrogenase (LDH) was found to be elevated in all cases. Serum alkaline phosphatase (ALP) was elevated in all except 1 case. Median overall survival (OS) was 91 days. BM involvement from solid organ cancer in adults predicts a poor outcome. Serum LDH and serum ALP can serve as a marker of BM involvement.

Healing of Ocular Herpetic Disease Following Treatment With an Engineered FGF-1 Is Associated With Increased Corneal Anti-Inflammatory M2 Macrophages.

Herpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.

Leptomeningeal relapse in primary cutaneous DLBCL: Implications for a prophylactic CNS therapy.

BACKGROUND: Isolated leptomeningeal relapse in a case of cutaneous lymphoma is an uncommon event more so in a case of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL). This phenomenon is of great significance as the subsequent prognosis becomes poor and the prophylactic central nervous system (CNS) therapy if administered, can reduce the chances of relapse, however, the survival benefit remains uncertain. The role of prophylactic CNS therapy is not well defined in the case of PCDLBCL. CASE: We report a case of PCDLBCL leg type with a low CNS International Prognostic Index (CNS-IPI) risk, who developed isolated leptomeningeal relapse in the form of bilateral facial nerve palsy. He was managed by 2nd line chemotherapy and CNS directed therapy and achieved complete remission. CONCLUSION: PCDLBCL leg type is an aggressive malignancy. Molecular/genomic mechanism likely responsible for CNS dissemination should be identified by prospective multi-centric studies that can better define the subsets of patients eligible for prophylactic therapy in the absence of a high CNS-IPI risk.

DFT Study on the Electronic Properties, Spectroscopic Profile, and Biological Activity of 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole with Anticancer Properties.

Extensive investigation on the molecular and electronic structure of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole in the ground state and in the first excited state has been performed. The energy barrier corresponding to the conversion between imino and amino tautomers has been calculated, which indicates the existence of amino tautomer in solid state for the title compound. The FT-Raman and FT-IR spectra were recorded and compared with theoretical vibrational wavenumbers, and a good coherence has been observed. The MESP map, dipole moment, polarizability, and hyperpolarizability have been calculated to comprehend the properties of the title molecule. High polarizability value estimation of the title compound may enhance its bioactivity. Natural bonding orbital analysis has been done on monomer and dimer to investigate the charge delocalization and strength of hydrogen bonding, respectively. Strong hydrogen bonding interaction energies of 17.09/17.49 kcal mol-1 have been calculated at the B3LYP/M06-2X functional. The UV-vis spectrum was recorded and related to the theoretical spectrum. The title compound was biologically examined for anticancer activity by studying the cytotoxic performance against two human cancer cell lines (A549 and HeLa) along with the molecular docking simulation. Both molecular docking and cytotoxic performance against cancer cell lines show positive outcomes, and the title compound appears to be a promising anticancer agent.

High Frequency of Gamma Interferon-Producing PLZFloRORγtlo Invariant Natural Killer 1 Cells Infiltrating Herpes Simplex Virus 1-Infected Corneas Is Associated with Asymptomatic Ocular Herpesvirus Infection.

Invariant natural killer (iNKT) cells are among the first innate immune cells to elicit early protective immunity that controls invading viral pathogens. The role of the iNKT cell subsets iNKT1, iNKT2, and iNKT17 in herpesvirus immunity remains to be fully elucidated. In this study, we examined the protective role of cornea-resident iNKT cell subsets using the mouse model of ocular herpesvirus infection and disease. Wild-type (WT) C57BL/6 (B6) mice and CD1d knockout (KO) mice were infected ocularly with herpes simplex virus 1 (HSV-1) (strain McKrae). Cornea, spleen, and liver were harvested at 0, 2, 5, 8, and 14 days postinfection (p.i.), and the frequency and function of the three major iNKT cell subsets were analyzed and correlated with symptomatic and asymptomatic corneal herpesvirus infections. The profiles of 16 major pro- and anti-inflammatory cytokines were analyzed in corneal lysates using Western blot and Luminex assays. Early during ocular herpesvirus infection (i.e., day 2), the gamma interferon (IFN-γ)-producing PLZFloRORγtlo (promyelocytic leukemia zinc finger, retinoic acid-related orphan receptor gT) iNKT1 cell subset was the predominant iNKT cell subset in infected asymptomatic corneas. Moreover, compared to the asymptomatic corneas of HSV-1-infected WT mice, the symptomatic corneas CD1d KO mice, with iNKT cell deficiency, had increased levels of the inflammatory cytokine interleukin-6 (IL-6) and decreased levels of IL-12, IFN-γ, and the JAK1, STAT1, NF-κB, and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways. Our findings suggest that IFN-γ-producing PLZFloRORγtlo iNKT1 cells play a role in the protective innate immune response against symptomatic ocular herpes.IMPORTANCE We investigated the protective role of iNKT cell subsets in asymptomatic ocular herpesvirus infection. We found that early during ocular herpesvirus infection (i.e., on day 2 postinfection), IFN-γ-producing PLZFloRORγtlo iNKT1 cells were the predominant iNKT cell subset in infected corneas of asymptomatic B6 mice (with little to no corneal herpetic disease), compared to corneas of symptomatic mice (with severe corneal herpetic disease). Moreover, compared to asymptomatic corneas of wild-type (WT) B6 mice, the symptomatic corneas of CD1d KO mice, which lack iNKT cells, showed (i) decreases in the levels of IFN-γ and IL-12, (ii) an increase in the level of the inflammatory cytokine IL-6; and (iii) downregulation of the JAK1, STAT1, NF-κB, and ERK1/2 pathways. The findings suggest that early during ocular herpesvirus infection, cornea-resident IFN-γ-producing PLZFloRORγtlo iNKT1 cells provide protection from symptomatic ocular herpes.

Metabolic syndrome and periodontal disease: An overview for physicians.

The metabolic syndrome (MetS) (also known as insulin resistance syndrome, syndrome X) is a cluster of factors associated with increased risk of developing coronary heart disease or type 2 diabetes mellitus. Several studies in the past have reviewed an association between MetS and periodontitis. Periodontal disease is considered an infectious and chronic inflammatory disease, and it has been considered to be a potential risk in cardiovascular and respiratory diseases and diabetes, and has implications in adverse pregnancy outcomes, osteoporosis, and so on. These systemic disorders have been documented as capable of affecting the periodontium or treatment of periodontal disease. Oral inflammatory lesions have different basic mechanisms concerning the possible association with systemic diseases. They concern local spread, metastatic spread, or immunologic cross-reactivity. In many studies, sometimes contrasting, periodontal pathogens have been evaluated in atheromatous plaques isolated from patients with chronic periodontitis. Oral inflammatory lesions have been shown unequivocally to contribute to elevated systemic inflammatory responses. In some studies, intensive periodontal therapy showed a significant reduction in c-reactive protein levels, interleukin-6, and low-density lipoprotein cholesterol after 2 months. The aim of this article is to reflect the association between MetS and periodontitis and to suggest an understanding to promote interprofessional practice; with proper oral care and plaque control, we can reduce the severity of MetS.

Efficacy of Platelet-rich Fibrin in Interdental Papilla Reconstruction as Compared to Connective Tissue Using Microsurgical Approach.

AIM: This study aims to evaluate autologous platelet-rich fibrin (PRF) and autogenous connective tissue graft (CTG) in interdental papilla (IDP) reconstruction with buccal and palatal split-thickness flap (STF) using microsurgical technique. MATERIALS AND METHODS: Forty Class I or Class II open gingival or cervical embrasure in maxillary anterior region in 14 patients were surgical treated for the reconstruction of IDP. For experimental Group I (STF with PRF, n = 20), surgical site was flushed with PRF fluid. PRF was then placed under the buccal flap and in the IDP region and squeezed. For experimental Group II (STF with CTG, n = 20) after the preparation of recipient site, CTG procured from palate was trimmed to the desired size and shape and placed at the site. Clinical parameters and patient satisfaction response recorded were plaque index, gingival index, probing pocket depth, clinical attachment level, height of IPD, and papilla index score (PIS). RESULTS: STF surgery in combination with PRF or CTG, are an effective procedure to increase IDP-height with mean values of 3.10 mm (87.3%) and 3.45 mm (95.8%) for Group I (STF + PRF) and Group II (STF + CTG), respectively. In terms of complete fill (CF) achieved at 3 months, in the present study, the result showed that 90% CF was obtained in Group I (STF + PRF) and 95% in Group II (STF + CTG). The patient response and acceptance for surgical treatment modality in terms of patient postsurgical discomfort score and patient esthetic score was higher for Group II (STF + CTG) than Group I (STF + PRF). CONCLUSION: Based on single-centered 3 months' follow-up, it may be concluded that STF surgery in combination with PRF or CTG is an effective procedure to increase IDP-height; however, a long-term multicentric randomized clinical trial may be necessary to evaluate the clinical outcome for autologous PRF in comparison to CTG with STF.

Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes.

HSV type 1 (HSV-1)-specific CD8+ T cells protect from herpes infection and disease. However, the nature of protective CD8+ T cells in HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (with no history of clinical herpes disease) remains to be determined. In this study, we compared the phenotype and function of HSV-specific CD8+ T cells from HLA-A*02:01-positive ASYMP and symptomatic (SYMP) individuals (with a documented history of numerous episodes of recurrent ocular herpetic disease). We report that although SYMP and ASYMP individuals have similar frequencies of HSV-specific CD8+ T cells, the "naturally" protected ASYMP individuals have a significantly higher proportion of multifunctional HSV-specific effector memory CD8+ T cells (CD73+CD45RAhighCCR7lowCD8+ effector memory RA (TEMRA) and CD73+CD45RAlowCCR7lowCD8+ effector memory (TEM) as compared with SYMP individuals. Similar to humans, HSV-1-infected ASYMP B6 mice had frequent multifunctional HSV-specific CD73+CD8+ T cells in the cornea, as compared with SYMP mice. Moreover, in contrast to wild type B6, CD73-/- deficient mice infected ocularly with HSV-1 developed more recurrent corneal herpetic infection and disease. This was associated with less functional CD8+ T cells in the cornea and trigeminal ganglia, the sites of acute and latent infection. The phenotypic and functional characteristics of HSV-specific circulating and in situ CD73+CD8+ T cells, demonstrated in both ASYMP humans and mice, suggest a positive role for effector memory CD8+ T cells expressing the CD73 costimulatory molecule in the protection against ocular herpes infection and disease. These findings are important for the development of safe and effective T cell-based herpes immunotherapy.

Human Asymptomatic Epitope Peptide/CXCL10-Based Prime/Pull Vaccine Induces Herpes Simplex Virus-Specific Gamma Interferon-Positive CD107+ CD8+ T Cells That Infiltrate the Corneas and Trigeminal Ganglia of Humanized HLA Transgenic Rabbits and Protect against Ocular Herpes Challenge.

Herpes simplex virus 1 (HSV-1) is a prevalent human pathogen that infects the cornea, causing potentially blinding herpetic disease. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull vaccine was tested in a human leukocyte antigen (HLA) transgenic rabbit model of ocular herpes (HLA Tg rabbits). Three peptide epitopes were selected, from the HSV-1 membrane glycoprotein C (UL44400-408), the DNA replication binding helicase (UL9196-204), and the tegument protein (UL25572-580), all preferentially recognized by CD8+ T cells from "naturally protected" HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were immunized with a mixture of these three ASYMP CD8+ T cell peptide epitopes (UL44400-408, UL9196-204, and UL25572-580), which were delivered subcutaneously with CpG2007 adjuvant (prime). Fifteen days later, half of the rabbits received a topical ocular treatment with a recombinant neurotropic adeno-associated virus type 8 (AAV8) vector expressing the T cell-attracting CXCL10 chemokine (pull). The frequency and function of HSV-specific CD8+ T cells induced by the prime/pull vaccine were assessed in the peripheral blood, cornea, and trigeminal ganglion (TG). Compared to the cells generated in response to peptide immunization alone, the peptide/CXCL10 prime/pull vaccine generated frequent polyfunctional gamma interferon-positive (IFN-γ+) CD107+ CD8+ T cells that infiltrated both the cornea and TG. CD8+ T cell mobilization into the cornea and TG of prime/pull-vaccinated rabbits was associated with a significant reduction in corneal herpesvirus infection and disease following an ocular HSV-1 (strain McKrae) challenge. These findings draw attention to the novel prime/pull vaccine strategy for mobilizing antiviral CD8+ T cells into tissues to protect against herpesvirus infection and disease.IMPORTANCE There is an urgent need for a vaccine against widespread herpes simplex virus infections. The present study demonstrates that immunization of HLA transgenic rabbits with a peptide/CXCL10 prime/pull vaccine triggered mobilization of HSV-specific CD8+ T cells locally into the cornea and TG, the sites of acute and latent herpesvirus infections, respectively. Mobilization of antiviral CD8+ T cells into the cornea and TG of rabbits that received the prime/pull vaccine was associated with protection against ocular herpesvirus infection and disease following an ocular HSV-1 challenge. These results highlight the importance of the prime/pull vaccine strategy to bolster the number and function of protective CD8+ T cells within infected tissues.

Patient-centered Microsurgical Management of Gingival Recession using Coronally Advanced Flap with Either Platelet-rich Fibrin or Connective Tissue Graft: A Comparative Analysis.

PURPOSE: To evaluate autologous platelet-rich fibrin (PRF) and autogenous connective tissue graft (CTG) in gingival recession defects in conjunction with coronally advanced flap (CAF) using a microsurgical technique. MATERIALS AND METHODS: Forty-five Class I and II recession defects were randomly equally (n = 15) divided into three groups: Group I sites treated with CAF with PRF, Group II sites treated with CAF with CTG, and Group III sites treated with CAF alone using microsurgical approach. Parameters recorded were vertical gingival recession (VGR) and horizontal gingival recession (HGR), % complete root coverage (CRC), patient comfort score (PCS), patient esthetic score (PES), and hypersensitivity score (HS) at 10 days, 3 months, and 6 months. RESULTS: CAF surgery alone and in combination with PRF or CTG are effective procedures to cover denuded roots with mean VGR values of 1.26 ± 0.70 mm (74.4%), 1.26 ± 0.59 mm (58%), and 1.06 ± 0.79 mm (53.3%) for Groups I, II, and III, respectively. In terms of CRC achieved at 6 months, results showed that 100% CRC was obtained in 60% sites of Group I, 20% sites of Group II, and 27% sites of Group III. Patient response and acceptance for surgical treatment modality in terms of PCS and PES were highest for Group I (PRF and CAF) followed by Group III and Group II, and there was decrease in HS for Group I (PRF and CAF) while no significant changes in HS were observed for Group II and Group III. At the end of 6 months follow-up, there was a significant increase in gingival thickness measurements using transgingival probing in Group II, whereas nonsignificant changes were observed in Group I and Group III. CONCLUSIONS: A long-term multicenter randomized controlled clinical study may be necessary to evaluate the clinical outcome for autologous PRF in comparison to CTG and CAF alone.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8+ TEM and CD8+ TRM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease.

Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8+ T cells play a critical role in preventing HSV-1 reactivation from TG and subsequent virus shedding in tears that trigger recurrent corneal herpetic disease. The CXC chemokine ligand 10 (CXCL10)/CXC chemokine receptor 3 (CXCR3) chemokine pathway promotes T cell immunity to many viral pathogens, but its importance in CD8+ T cell immunity to recurrent herpes has been poorly elucidated. In this study, we determined how the CXCL10/CXCR3 pathway affects TG- and cornea-resident CD8+ T cell responses to recurrent ocular herpesvirus infection and disease using a well-established murine model in which HSV-1 reactivation was induced from latently infected TG by UV-B light. Following UV-B-induced HSV-1 reactivation, a significant increase in both the number and function of HSV-specific CXCR3+ CD8+ T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10-/- or CXCR3-/- deficient mice. This increase was associated with a significant reduction in both virus shedding and recurrent corneal herpetic disease. Furthermore, delivery of exogenous CXCL10 chemokine in TG of CXCL10-/- mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8+ T cells (TEM) and tissue-resident memory CD8+ T cells (TRM), but not of central memory CD8+ T cells (TCM), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10-/- deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8+ T cell immunity, locally within latently infected tissues, which protects against recurrent herpesvirus infection and disease.IMPORTANCE We determined how the CXCL10/CXCR3 pathway affects CD8+ T cell responses to recurrent ocular herpesvirus infection and disease. Using a well-established murine model, in which HSV-1 reactivation in latently infected trigeminal ganglia was induced by UV-B light, we demonstrated that lack of either CXCL10 chemokine or its CXCR3 receptor compromised the mobilization of functional CD8+ TEM and CD8+ TRM cells within latently infected trigeminal ganglia following virus reactivation. This lack of T cell mobilization was associated with an increase in recurrent ocular herpesvirus infection and disease. Inversely, augmenting the amount of CXCL10 in trigeminal ganglia of latently infected CXCL10-deficient mice significantly restored the number of local antiviral CD8+ TEM and CD8+ TRM cells associated with protection against recurrent ocular herpes. Based on these findings, a novel "prime/pull" therapeutic ocular herpes vaccine strategy is proposed and discussed.

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy.

Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1ß, and IL-18 in the quadriceps muscles of VCPR155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1ß(+)F4/80(+)Ly6C(+) inflammatory macrophages that infiltrate the muscles of VCPR155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1ß(+)F4/80(+)Ly6C(+) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCPR155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80(+)Ly6C(+)IL-1ß(+) macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1ß(+)F4/80(+)Ly6C(+) inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection.

Herpes simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8+ T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8+ T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8+ T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8+ T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107a/b cytotoxic degranulation. High frequencies of multifunctional CD8+ T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14286-294), VP13/14 from amino acids 504 to 512 (VP13/14504-512), and VP13/14 from amino acids 544 to 552 (VP13/14544-552), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RAlow CD44high CCR7low CD62Llow CD8+ effector memory T cells (TEM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8+ TEM-cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8+ TEM cells associated with strong protective immunity against ocular herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8+ T cells that should guide the development of a safe and effective T-cell-based herpes simplex vaccine. IMPORTANCE: Although most herpes simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8+ T cells (CD8+ TEM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14286-294,VP13/14504-512, and VP13/14544-552) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8+ TEM-cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8+ T cells associated with strong protective immunity against ocular herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic herpes simplex vaccine that is selectively based on CD8+ T-cell epitopes from ASYMP individuals.

Nasal Polyp - An Incidental Paraganglioma.

The nose is an uncommon site for head and neck paraganglioma. The diagnosis is seldom established pre-operatively; its rarity, infrequent functionality and often benign biologic outcome underlie this fact. We present one such case in a 60-year-old man who presented with right nasal obstruction and episodic epistaxis. Rhinoscopy revealed a fleshy polypoid mass arising from the anterior cartilaginous nasal septum. Imaging studies excluded extra-nasal extension. The tumor was highly vascular showing numerous variable sized, mostly thin walled branching blood vessels akin to stag-horn shape simulating a vascular neoplasm. There were large areas of hyalinization. The typical tumor morphology was discernible only in focal areas. Immuno-histochemistry confirmed the diagnosis. The tumor cells expressed neuron specific enolase; S-100 stain demonstrated a vague zell-ballen pattern. Paraganglioma is a rare histologic diagnosis in nasal polypectomy specimen. We discuss the approach to exclude its morphologic mimics including vascular tumors.

The Herpes Simplex Virus Latency-Associated Transcript Gene Is Associated with a Broader Repertoire of Virus-Specific Exhausted CD8+ T Cells Retained within the Trigeminal Ganglia of Latently Infected HLA Transgenic Rabbits.

UNLABELLED: Persistent pathogens, such as herpes simplex virus 1 (HSV-1), have evolved a variety of immune evasion strategies to avoid being detected and destroyed by the host's immune system. A dynamic cross talk appears to occur between the HSV-1 latency-associated transcript (LAT), the only viral gene that is abundantly transcribed during latency, and the CD8(+)T cells that reside in HSV-1 latently infected human and rabbit trigeminal ganglia (TG). The reactivation phenotype of TG that are latently infected with wild-type HSV-1 or with LAT-rescued mutant (i.e., LAT(+)TG) is significantly higher than TG latently infected with LAT-null mutant (i.e., LAT(-)TG). Whether LAT promotes virus reactivation by selectively shaping a unique repertoire of HSV-specific CD8(+)T cells in LAT(+)TG is unknown. In the present study, we assessed the frequency, function, and exhaustion status of TG-resident CD8(+)T cells specific to 40 epitopes derived from HSV-1 gB, gD, VP11/12, and VP13/14 proteins, in human leukocyte antigen (HLA-A*0201) transgenic rabbits infected ocularly with LAT(+)versus LAT(-)virus. Compared to CD8(+)T cells from LAT(-)TG, CD8(+)T cells from LAT(+)TG (i) recognized a broader selection of nonoverlapping HSV-1 epitopes, (ii) expressed higher levels of PD-1, TIM-3, and CTLA-4 markers of exhaustion, and (iii) produced less tumor necrosis factor alpha, gamma interferon, and granzyme B. These results suggest a novel immune evasion mechanism by which the HSV-1 LAT may contribute to the shaping of a broader repertoire of exhausted HSV-specific CD8(+)T cells in latently infected TG, thus allowing for increased viral reactivation. IMPORTANCE: A significantly larger repertoire of dysfunctional (exhausted) HSV-specific CD8(+)T cells were found in the TG of HLA transgenic rabbits latently infected with wild-type HSV-1 or with LAT-rescued mutant (i.e., LAT(+)TG) than in a more restricted repertoire of functional HSV-specific CD8(+)T cells in the TG of HLA transgenic rabbits latently infected with LAT-null mutant (i.e., LAT(-)TG). These findings suggest that the HSV-1 LAT locus interferes with the host cellular immune response by shaping a broader repertoire of exhausted HSV-specific CD8(+)T cells within the latency/reactivation TG site.