Macrophage CD5L is a target for cancer immunotherapy.

BACKGROUND: Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target. METHODS: Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR. FINDINGS: Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel-Cox) test p = 0.02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages in vitro. Its administration in vivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4+ T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu. INTERPRETATION: CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy. FUNDING: For a full list of funding bodies, please see the Acknowledgements.

The effect of chlorhexidine gluconate chips on clinical status of peri-implant mucosa and plaque formation on healing abutments following single-stage implant surgeries.

Background: An experimental study was designed to evaluate the effect of chlorhexidine gluconate chips on clinical status of peri-implant mucosa and plaque formation on healing abutments following single-stage implant surgeries. Materials and Methods: Twenty-eight single-stage implant sites were grouped into 14 test and control sites. The study commences from the time of suture removal following surgery, designated as day 0. Chlorhexidine chip insertion into peri-implant sulcus in test sites was done on day 0, 10, and 20. Peri-implant crevicular fluid was collected on day 0, 10, 20, and 30 for biochemical estimation of aspartate aminotransferase (AST). The modified sulcus bleeding index (mBI) score was obtained in both test and control sites on day 10, 20, and 30. On day 30, all the healing abutments were unscrewed and sent for stereomicroscopic analysis to assess the plaque formation on its surface. Results: Statistically significant difference was not observed in AST levels and mBI in both test and control groups in various time intervals. In the stereomicroscopic assessment of healing abutment, mild grade of plaque accumulation was seen in three samples in test group, one sample in control group, and severe grade was seen in six samples in test group and nine samples in the control group. Conclusion: Inflammatory condition of peri-implant mucosa and plaque retentive properties on healing abutment surface were found to have reduced with the usage of chlorhexidine gluconate chips. However, the study failed to establish a statistically significant correlation of these observations.

Macrophages as a Therapeutic Target in Metastatic Prostate Cancer: A Way to Overcome Immunotherapy Resistance?

Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs.

Multifaceted Roles of CD5L in Infectious and Sterile Inflammation.

CD5L, a protein expressed and secreted mainly by macrophages, is emerging as a critical immune effector. In addition to its well-defined function as an anti-apoptotic protein, research over the last decade has uncovered additional roles that range from pattern recognition to autophagy, cell polarization, and the regulation of lipid metabolism. By modulating all these processes, CD5L plays a key role in highly prevalent diseases that develop by either acute or chronic inflammation, including several infectious, metabolic, and autoimmune conditions. In this review, we summarize the current knowledge of CD5L and focus on the relevance of this protein during infection- and sterile-driven inflammatory pathogenesis, highlighting its divergent roles in the modulation of inflammation.

Comparative Evaluation of Different Soft Tissue Coverage Techniques at Immediate Implant Sites: A Cohort Study.

AIM AND OBJECTIVE: To compare the mucosal thickness, width of attached gingiva, and extent of coverage achieved with the usage of connective tissue graft, platelet-rich fibrin (PRF) membrane and buccally advanced flap along with bone grafts in the closure of immediate implant site. MATERIALS AND METHODS: Twenty-one sites requiring immediate implants were randomly divided into three groups of seven samples each. The techniques comprised bone grafting in jumping space along with either buccally advanced flap (group A), PRF membrane (group B), or connective tissue graft (group C) to cover the socket. In each group, the extent of socket coverage, mucosal phenotype, and width of attached mucosa achieved were assessed after 3 months and intercompared with initial measurements to identify the best technique in achieving primary tissue closure of immediate implant sites. RESULTS: Comparative assessment of gain in attached mucosal width had a remarkable difference in all the groups but exhibited no statistical significance among the groups compared. Also, comparative assessment of mucosal thickness and the extent of socket coverage equally indicated a clinical significance among all groups, but failed to achieve any statistical significance. CONCLUSION: All the three techniques were found to be equally effective in achieving additional width of attached mucosa around implants, coverage of mucosa at osteotomy sites, and a thicker mucosal phenotype at implant sites. In comparison with one another, no single technique was found to be advantageous over the other. CLINICAL SIGNIFICANCE: The commonly used three techniques for socket coverage following the immediate implant placement has been proven to be equally effective. Thus, the selection of the technique to meet the objective of complete closure of an extraction socket along with implant platform is left open to operator skill and operation site, which should consider least traumatic and most feasible technique.

Comparative evaluation of the effect of Ozone therapy and Photodynamic therapy in non-surgical management of Chronic periodontitis: A split mouth longitudinal study.

BACKGROUND: A split-mouth longitudinal study was conducted to compare and evaluate the effect of ozonated water and photodynamic therapy (PDT) in nonsurgical management of chronic periodontitis, along with mechanical debridement procedure. MATERIALS AND METHODS: Twenty-two patients diagnosed with chronic generalized periodontitis were subjected to the study. Following the assessment of gingival index, periodontal pocket depth, and clinical attachment loss, all patients underwent full-mouth scaling and root planing. Upper right and left quadrants of each patient were considered as sample sites in the study. Among these split-mouth sites, upper right quadrant of each patient was subjected to ozonated water irrigation with a 22-gauge needle and left upper quadrant was treated with PDT, which involved sulcus irrigation with indocyanine green dye (0.05 mg/ml) followed by low-level diode laser light application at 0.5 W and 810 nm (AMD Picasso) through a fiber-optic tip of 10 mm length, default angle of 60°, and fiber core diameter of 400 µm in noncontact continuous wave mode. Patients were recalled at the 2nd and 4th months regularly, and the therapy was repeated at the same sites in the same manner. Clinical parameters recorded before the study were assessed again at the end of the 2nd- and 6th-month period. RESULTS: A statistically significant reduction (P < 0.05) was observed in gingival index scores within both the study groups at all intervals of the study. In Ozone therapy (OT) group, a statistically significant difference was noted for total periodontal pocket depth values between baseline and 2nd month (P = 0.000), baseline and 6th month (P = 0.000), and between 2nd month and 6th month (P = 0.029). In the PDT group, on contrary, a statistically significant difference was noticed in total periodontal pocket probing depth values between baseline and 2nd month (P = 0.000) and baseline to 6th month (P = 0.000), but a similar significant difference was not noticed between 2nd-month and 6th-month periods (P = 0.269). In group OT, a statistically significant difference was noted for total clinical attachment loss between baseline and 2nd month (P = 0.000), baseline and 6 months (P = 0.000), and 2nd month and 6th month (P = 0.019). In group PDT, a statistically significant difference in terms of its improvement was noted at intervals between baseline and 2 months (P = 0.000) and from baseline to 6 months (P = 0.000) but not between 2nd month and 6th month (P = 0.129). CONCLUSION: Results of the study showed that sub-gingival OT and PDT equally improved the clinical outcomes of treatment drastically following mechanical debridement at the end of first 2 months. Thereafter, it was shown to improve steadily throughout the study period, with slightly better results with OT compared with PDT.

Assessment of the effect of ozonated water irrigation on gingival inflammation in patients undergoing fixed orthodontic treatment.

BACKGROUND: A split-mouth longitudinal study was designed here to evaluate the effect of ozonated water delivered subgingivally through a jet device (Kent Ozone dental TY 820 jet) in controlling gingival inflammation of patients undergoing fixed orthodontic therapy. MATERIALS AND METHODS: Twenty-eight patients undergoing fixed orthodontic treatment following thorough oral prophylaxis were recalled after 2 weeks, and baseline gingival inflammation was estimated. This study was conducted as split-mouth technique with the upper left quadrant (Control side) was irrigated by jetting saline into sulcus by air-water syringe with gauge 22 needle tip and upper right quadrant (Test side) irrigated with ozonated water by a jet device using similar delivery tip. The patients were recalled at the end of 1st, 2nd, 3rd, and 4th month and the irrigations as well as gingival inflammation estimation were repeated. A biochemical assessment of gingival inflammation (estimation of aspartate aminotransferase [AST] in gingival crevicular fluid [GCF]) and clinical assessment (gingival index scoring) was done at each visit. RESULTS: At the test side, the AST level in the GCF was found to be maintained almost the same value as baseline till the end of 4th month, indicating not much of change in inflammatory status. Statistically significant difference in GCF-AST and gingival index score between test and control sites were found at the end of 3rd and 4th month with a significance of P < 0.05. CONCLUSION: The patient undergoing fixed orthodontic treatment showed a consistent improvement in gingival inflammation on frequent irrigation with ozone jet irrigation as compared with saline irrigation delivered with same jetting force.

Benign schwannoma of the maxillary antrum.

Schwannoma also known commonly as neurilemmoma and schwann cell tumor is a benign nerve sheath tumor. About 1/3(rd) cases of schwannoma arise from the head and neck region but rarely from the nasal and paranasal sinuses. The recurrence rate in these cases has reported to be very rare. We report a rare case of schwannoma in a 60-year-old woman arising from the maxillary sinus further eroding the orbital floor and nasal bone. We have also described the clinical presentation, radiological, histological findings, and management of the case.

Comparative Evaluation of Sustained Release Collagen Device Containing 5% Metronidazole (Metrogene) along With and Without Scaling and Root Planing at Regular Intervals with Treatment of Chronic Periodontitis: A Case Control Study.

BACKGROUND: A short-term study was undertaken with an objective to demonstrate the therapeutic benefit resulting from the use of Metronidazole sponges combined with and without mechanical debridement to mechanical treatment alone in the treatment of periodontal pockets in chronic periodontitis. MATERIALS AND METHODS: The study compared the plaque index, gingival index, sulcus bleeding index and probing pocket depth in twenty control sites that received superficial scaling and root planing without the local drug delivery with experimental site A (20 sites that received local drug delivery (5% metronidazole) without superficial scaling and root planing) and experimental site B (20 sites received superficial scaling, root planing and local drug delivery (5% metronidazole) at "0" day, 15(th) day and 30(th) day. RESULTS: There was a significant reduction in plaque index, gingival index, sulcus bleeding index and probing pocket depth in both experimental sites A and B at different intervals from the baseline. CONCLUSION: From the above conclusions, it can be suggested that a single subgingival application of 5% metronidazole in a collagen carrier can be effective, when associated with debridement in the treatment of adult periodontitis.

A combined periodontal - prosthetic treatment approach to manage unusual gingival visibility in resting lip position and inversely inclined upper anterior teeth: a case report with discussion.

Excessive gingival visibility during smile is a common esthetic complaint in dentistry, but excessive gingival visibility in resting lip position is relatively uncommon condition. Several exclusive radical to conservative surgical treatment or its combination with orthodontic therapy to treat this condition are within the reach of every patient nowadays. A case report of an excessive gingival visibility because of altered passive eruption along with inversely inclined maxillary anterior teeth is presented here. A relatively simple treatment approach combining periodontal and restorative therapy is used here to achieve the desirable aesthetic results. The gingival exposure resulting from altered passive eruption was completely managed by a gingivectomy, but the inclined appearance of teeth was still an aesthetic complaint. After complete healing of gingivectomy surgery, appropriately designed crowns were given to rectify the inversely inclined appearance. A complete rehabilitation of patient's smile could be achieved, the case was followed up for 3 years and the condition was found satisfactory.