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Three labdane-type diterpenes, namely coronalactoside I, hedychilactone A, and ( E )-labda-8(17),12-dien-15(16)-olide, along with the flavonoid glycoside Isolinariin A, were isolated from Heydichium coronarium . Structural elucidation employed spectroscopic techniques (IR, MS, NMR, and DEPT) and comparison with literature data. Pesticidal and antimicrobial activities were assessed. Isolinariin A exhibited potent nematicidal activity (71.33% mortality) against Meloidogyne incognita , while Coronalactoside I demonstrated strong inhibition of nematode egg hatchability (26.00% at 1 µg/mL). In insecticidal activity against Spodoptera litura , ( E )-labda-8(17),12-dien-15(16)-olide displayed significant mortality (93.66% at 100 µg/mL). Molecular docking studies indicated favourable interactions with target proteins, suggesting potential in pest management. These findings propose the application of these compounds to mitigate the ecological impact of synthetic pesticides.

The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early-onset CRC [EOCRC]) has substantially increased, and yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T-cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020. EOCRC was defined as younger than age 50 years at diagnosis (N = 126) and AOCRC as 60 years of age or older (N = 116). T-cell receptor (TCR) abundance and clonality were measured by immunosequencing of tumors. Logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 EOCRC and 1984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study. EOCRC tumors had significantly higher TCR diversity compared with AOCRC tumors in the discovery cohort (odds ratio [OR] = 0.44, 95% confidence interval [CI] = 0.32 to 0.61, P < .0001). This association was also observed in the replication cohort (OR = 0.74, 95% CI = 0.62 to 0.89, P = .0013). No significant differences in TCR abundance were observed between EOCRC and AOCRC in either cohort. Higher TCR diversity, suggesting a more diverse intratumoral T-cell response, is more frequently observed in EOCRC than AOCRC. Further studies are warranted to investigate the role of T-cell diversity and the adaptive immune response more broadly in the etiology and outcomes of EOCRC., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Prcis: Reading results in a rise in intraocular pressure (IOP) which is greater while using smartphones compared with printed text among healthy and individuals with medically controlled primary open angle glaucoma (POAG)., Purpose: To compare the effect of reading for 30 minutes using smartphone and printed text on IOP., Patients and Methods: Sixty healthy volunteers and 22 patients with medically controlled POAG were asked to perform reading tasks using printed text followed by digital (smartphone) text under standardized conditions. IOP assessment was done using a rebound tonometer at baseline and subsequently at 10, 20, and 30 minutes of reading and 10 and 20 minutes post completion of reading tasks. IOP variations from baseline were measured and compared. Paired and independent ' T ' test analysis was performed to study IOP variations, and a P -value <0.05 was considered statistically significant., Results: The mean baseline IOP among volunteers and patients withPOAG was 14.58 (±2.91) and 15.02 (±2.18) mmHg, respectively. There was a rise in IOP in all participants with reading using either of the modalities, which normalized after 20 minutes of cessation. There was a statistically significant difference in rise in IOP from baseline between the 2 modalities (printed text reading and smartphone reading) at 20 minutes {+0.78 & +2.01 ( P =0.002)} and 30 minutes {+0.64 & +1.72 ( P =0.004)} among healthy volunteers and at 20 minutes {+0.78 & +2.01 ( P =0.002)} among POAG patients., Conclusion: Reading is associated with the rise in IOP in both healthy volunteers and POAG individuals. The IOP rise is more marked with smartphone compared with printed text reading., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes. Whereas wild-type TAMs exhibited inflammatory and angiogenic gene expression profiles, TSC1-deficient TAMs had a pro-resolving phenotype. TSC1-deficient TAMs relocated to a perivascular niche, depleted protein C receptor (PROCR)-expressing endovascular endothelial progenitor cells, and rectified the hyperpermeable blood vasculature, causing tumor tissue hypoxia and cancer cell death. TSC1-deficient TAMs were metabolically active and effectively eliminated PROCR-expressing endothelial cells in cell competition experiments. Thus, TAMs exhibit a TSC1-dependent mTORC1-low state, and increasing mTORC1 signaling promotes a pro-resolving state that suppresses tumor growth, defining an innate immune tumor suppression pathway that may be exploited for cancer immunotherapy., Competing Interests: Declaration of interests MSKCC has filed a patent application (number 63/502054) with the US Patent and Trademark Office directed toward targeting the mTORC1 signaling pathway in macrophages for cancer immunotherapy. M.O.L. is a scientific advisory board member of and holds equity or stock options in Amberstone Biosciences and META Pharmaceuticals., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Retinoblastoma makes up about 3% of all childhood malignancies. The frequency of metastatic retinoblastoma ranges from 4.8 to 11%. Assessing the bone marrow status of newly diagnosed patients is crucial because of the advantages of autologous bone marrow transplants for high-risk patients. This study aimed to determine the utility of bone marrow examination in cases of retinoblastoma and its correlation with hematological findings. This retrospective study was conducted at the Department of Pathology, King George's Medical University, Lucknow, India. A total of 34 cases of retinoblastoma with bone marrow examination were included in the study. Bone marrow infiltration was present in 17.65% (6/34) cases of retinoblastoma. Bone marrow aspirate myelogram showed that marrow metastasis in retinoblastoma was significantly linked with a reduced percentage of total myeloid cells (p=0.001) and segmented cells (p=0.006). The present study demonstrated that 15% (3/20) of retinoblastoma patients previously classified as nonmetastatic before bone marrow examination (stages I to III based on histology, imaging, and bone scan) had bone marrow metastases following bone marrow examination and were upgraded to stage IV. To conclude, a diligent and exhaustive search for metastatic cells in bone marrow is advised if the myelogram shows a reduced percentage of total myeloid and segmented cells. All stage II and stage III cases of retinoblastoma must undergo bone marrow examination for early metastasis detection, as it may result in an upgrade to stage IV disease, impacting the prognosis and necessitating distinct treatment modalities., Competing Interests: The authors declare no conflict of interest., (©2023 JOURNAL of MEDICINE and LIFE.)

The present study aimed to identify the bioactive constituents in the chloroform extract of H. spicatum rhizomes (HS-RCLE), further evaluated for its in-vitro pesticidal activities validating via molecular docking techniques. GC/MS analysis of HS-RCLE identified 14 compounds contributing 84.1 % of the total composition. The extract was dominated by oxygenated sesquiterpenes (43.1 %) with curcumenone (25.2 %) and coronarin E (14.8 %) as the major compounds. The extract recorded 89.4 % egg hatchability inhibition and 82.6 % immobility of Meloidogyne incognita, 66.7 % insecticidal activity on Spodoptera litura, 100 % phytotoxic activity on Raphanus raphanistrum seeds, and 74.7 % anti-fungal activity on Curvularia lunata at the respective highest dose studied. The biological activities were furthermore validated by using docking studies on certain proteins/enzymes namely acetylcholinesterase (PBD ID: IC2O), carboxylesterase (PDB ID: 1CI8), acetohydroxyacid synthase (PBD ID: 1YHZ) and trihydroxy naphthalene reductase (PBD ID: 3HNR). The bioactivity of the major constituents of the extract was predicted with the help of in silico PASS studies. HS-RCLE was observed to be a viable alternative source of natural pesticidal agents and paves the way for further studies on its mechanistic approaches and field trials to ascertain its pesticidal studies.

Purpose: Glaucoma is the second leading cause of blindness worldwide, affecting more than 64 million people aged 40-80. The best way to manage primary open-angle glaucoma (POAG) is by lowering the intraocular pressure (IOP). Netarsudil is a Rho kinase inhibitor, the only class of antiglaucoma medications that reorganizes the extracellular matrix to improve the aqueous outflow through the trabecular pathway., Methods: An open-label, real-world, multicentric, observation-based 3-month study was performed for assessing the safety and ocular hypotensive efficacy of netarsudil ophthalmic solution (0.02% w/v) in patients with elevated IOP. Patients were given netarsudil ophthalmic solution (0.02% w/v) as a first-line therapy. Diurnal IOP measurements, best-corrected visual acuity, and adverse event assessments were recorded at each of the five visits (Day-1: screening day and first dosing day; subsequent observations were taken at 2 weeks, 4 weeks, 6 weeks, and 3 months)., Results: Four hundred and sixty-nine patients from 39 centers throughout India completed the study. The mean IOP at baseline of the affected eyes was 24.84 ± 6.39 mmHg (mean ± standard deviation). After the first dose, the IOP was measured after 2, 4, and 6 weeks, with the final measurement taken at 3 months. The percentage reduction in IOP in glaucoma patients after 3 months of once-daily netarsudil 0.02% w/v solution use was 33.34%. The adverse effects experienced by patients were not severe in the majority of cases. Some adverse effects observed were redness, irritation, itching, and others, but only a small number of patients experienced severe reactions, as reported in a decreasing order: redness > irritation > watering > itching > stinging > blurring., Conclusion: We found that netarsudil 0.02% w/v solution monotherapy when used as the first-line treatment in primary open-angle glaucoma and ocular hypertension was both safe and effective., Competing Interests: None

Globba sessiliflora Sims is an aromatic rhizomatous herb of family Zingiberaceae which is endemic to Peninsular India. This study first reports the phytochemical profile and pesticidal potential of oleoresins obtained from the aerial and rhizome parts of Globba sessiliflora Sims. The oleoresins were prepared by the cold percolation method and were analyzed by a gas chromatography-mass spectrometry (GC-MS) method. Both the oleoresins varied greatly in composition, the major compounds identified in aerial part oleoresin (GSAO) were methyl linoleate, methyl palmitate, and phytol, while the major compounds present in rhizome part oleoresin (GSRO) were γ -sitosterol, 8 (17),12-labdadiene-15, 16-dial, methyl linoleate, and methyl palmitate. In order to evaluate the biological activities, the oleoresins were tested under laboratory conditions for nematicidal action and inhibition of egg hatching potential against root knot nematode, where GSRO was more effective. Insecticidal activity was performed against mustard aphid, Lipaphis erysimi and castor hairy caterpillar, Selepa celtis . In case of mustard aphid, GSRO (LC 50  = 154.8 ppm) was more effective than GSAO (LC 50  = 263.0 ppm), while GSAO (LC 50  = 346.7.0 ppm) was more effective against castor hairy caterpillar than GSRO (LC 50  = 398.1 ppm). The herbicidal activity was performed in the receptor species Raphanus raphanistrum subsp. sativus , and the oleoresins showed different intensities for seed germination inhibition and coleoptile and radical length inhibition. Molecular docking studies were conducted to screen the in vitro activities and through molecular docking, it was found that the major oleoresins components were able to interact with the binding pocket of HPPD and AChE with γ -sitosterol showing the best binding affinity., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Bhawna Verma et al.)

Tumors are populated by antigen-presenting cells (APCs) including macrophage subsets with distinct origins and functions. Here, we examined how cancer impacts mononuclear phagocytic APCs in a murine model of breast cancer. Tumors induced the expansion of monocyte-derived tumor-associated macrophages (TAMs) and the activation of type 1 dendritic cells (DC1s), both of which expressed and required the transcription factor interferon regulatory factor-8 (IRF8). Although DC1s mediated cytotoxic T lymphocyte (CTL) priming in tumor-draining lymph nodes, TAMs promoted CTL exhaustion in the tumor, and IRF8 was required for TAMs' ability to present cancer cell antigens. TAM-specific IRF8 deletion prevented exhaustion of cancer-cell-reactive CTLs and suppressed tumor growth. Tumors from patients with immune-infiltrated renal cell carcinoma had abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Smartphone photographs capturing Bruckner’s reflex have demonstrated reliability in identifying amblyogenic conditions in children. Assessing visual acuity for screening has been the traditional method since the inception of school screening. The present study aims to assess the reliability of smartphone photographs in detecting ocular morbidities in school children and to compare it with traditional vision screening. Two thousand five hundred and twenty school children underwent vision screening and smartphone cameraphotography by a trained research assistant followed by a comprehensive eye examination of all children by an ophthalmologist. Children with unaided visual acuity less than 6/12 in either of the eyes were graded as abnormal. Based upon the characteristics of the Bruckner’s reflex, the photographs were graded as normal or abnormal by two investigators blinded to the clinical findings. Statistical analysis was performed to compare the sensitivity and specificity of traditional vision screening and photograph based screening, considering comprehensive eye examination as the gold standard. The sensitivity and specificity of vision screening was 81.88% and 97.35% whereas for photographs it was 94.69% and 98.85% respectively. When the two methods were compared, the p value was <0.05. We conclude that smartphone photography is better than traditional vision screening for detecting ocular morbidities in school children.

Hedychium coccineum Buch. Ham. ex Sm. is a perennial rhizomatous herb belonging to the family Zingiberaceae. The aim of the present study was to compare the chemical composition and biological activities of H. coccineum rhizome essential oil (HCCRO) and H. coccineum aerial part essential oil (HCCAO). The plant material was subjected to hydro-distillation using Clevenger's apparatus in order to obtain volatile oil and analyzed for its chemical constituents using GC-MS. The comparative study of the rhizome and aerial part essential oils of H. coccineum displayed that ( E )-nerolidol (15.9%), bornyl acetate (13.95%), davanone B (10.9%), spathulenol (8.9%), and 1, 8-cineol (8.5%) contributed majorly to the HCCRO, while 7-hydroxyfarnesen (15.5%), α-farnesene (11.1%), α-pinene (10.9%), spathulenol (7.7%), and β-pinene (6.8%) were present as major constituents in the HCCAO. Both the essential oils were studied for their biological activities, such as nematicidal, insecticidal, herbicidal, antifungal, and antibacterial activities. The essential oils exhibited significant nematicidal activity against Meloidogyne incognita , insecticidal activity against Spodoptera litura , and moderate herbicidal activity against R. raphanistrum sub sp. sativus , and good antifungal activity against Fusarium oxysporum and Curvularialunata . Essential oils were also tested for antibacterial activity against Staphylococcus aureus and Salmonella enterica serotype Typhi. Both oils showed good to moderate activity against the tested pathogens. The significant nematicidal, insecticidal, herbicidal, antifungal, and antibacterial activities of both the essential oils might be helpful for the development of environmentally friendly pesticides that could be an alternative to synthetic pesticides in the future.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To assess the change in binocular summation (BiS) in comitant exotropia (XT) after strabismus surgery., Methods: This is a prospective study on 20 patients who underwent surgery for comitant XT over a one year period. Patients with sensory exotropia and nystagmus were excluded. Best-corrected visual acuity (VA) and contrast sensitivity (CS) of both eyes separately and together (binocularly) were recorded. BiS score was calculated as binocular score minus better eye score. BiS score at the end of 3 months was compared with the preoperative data., Results: The mean ± SD of BiS score increased from 2.95 ± 0.88 to 4.55 ± 0.68 (P-value < 0.0001) for VA (on ETDRS letters) and from 2.75 ± 0.44 to 4.5 ± 0.76 (P-value < 0.001 for CS (on Pelli-Robson chart) after surgery., Conclusion: There is significant improvement in BiS in XT after strabismus surgery. Authors recommend its inclusion in evaluation of functional outcome of XT surgery., Competing Interests: None

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.

The whitefly, Bemisia tabaci (Gennadius), is responsible for significant yield losses in many crops, including potato, by sucking the phloem sap and transmitting a number of plant viruses. B. tabaci is a complex of cryptic species which is commonly designated as genetic groups. The B. tabaci genetic groups differ biologically with respect to host plant preference, insecticidal resistance, reproduction capacity, and ability to transmit begomoviruses. Therefore, understanding genetic variation among populations is important for establishing crop-specific distribution profile and management. We sequenced the mitochondrial cytochrome oxidase I ( mtCOI ) gene of B. tabaci collected from major potato growing areas of India. BLAST analysis of the 24 mtCOI sequences with reference Gene Bank sequences revealed four B. tabaci genetic groups prevailing in this region. mtCOI analysis exhibited the presence of Asia II 1, Asia II 5, Asia 1, and MEAM1 B. tabaci genetic groups. Our study highlighted that a new genetic group Asia II 5 has been detected in Indo-Gangetic Plains. Further virus-vector relationship study of ToLCNDV with Asia II 5 B. tabaci revealed that females are efficient vector of this virus as compared to males. This behavior of females might be due to their ability to acquire more virus titer than males. This study will help in better understanding of whitefly genetic group mediated virus diseases., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest in the publication., (© King Abdulaziz City for Science and Technology 2021.)

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A + tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC., Competing Interests: Declaration of interests T.A.C. is a co-founder of Gritstone Oncology and holds equity. T.A.C. holds equity in An2H. T.A.C. acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai. T.A.C. has served as an advisor for Bristol-Myers Squibb, Illumina, Eisai, and An2H. M.S.K. has licensed the use of TMB for the identification of patients who benefit from immune checkpoint therapy to PGDx. S.W. holds equity in Illumina., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Context: Effect of fluid reflux on intraocular pressure (IOP) and therapeutic benefits., Aims: The aim of this study is to compare two intravitreal injection techniques in terms of fluid reflux, short-term IOP changes, and therapeutic effect., Settings and Design: A prospective, double-blinded, randomized interventional study., Subjects and Methods: Sixty eyes were randomly allocated to two groups (direct intravitreal injection technique and oblique intravitreal injection technique). IOP was measured before and immediately after the injection of 0.1 ml comprising of bevacizumab (1.25 mg/0.05 ml) and dexamethasone (0.2 mg/0.05 ml) and then at 30 min after the injection. Occurrence and amount of vitreous reflux were recorded. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) were assessed preinjection and 6 weeks postinjection., Results: IOP (mmHg ± standard deviation) increased significantly immediately after injection to 24.30 ± 3.02 (direct intravitreal injection) and 31.50 ± 3.49 (oblique intravitreal injection). These pressure rise differed significantly between both groups (mean difference: 7.2, P < 0.0001). Thirty minutes after injection, there was no significant difference in IOP increase between the groups. Occurrence and amount of fluid reflux were significantly higher with direct intravitreal injection. There was no significant difference in BCVA and CMT outcome between both groups., Conclusions: Direct intravitreal injection technique has lower rise in IOP and higher incidence of fluid reflux than the oblique intravitreal technique. Fluid reflux does not cause a therapeutic compromise in terms of BCVA or CMT changes, so the reflux fluid must be the vitreous not the drug. Thus, direct injection technique seems to be the preferred technique., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Oman Ophthalmic Society.)

Purpose: To compare the short-term outcome of botulinum neurotoxin A (BoNT-A) with or without sodium hyaluronate in the treatment of infantile esotropia (IE)., Methods: In this tertiary care hospital-based prospective, interventional, non-randomized study on infants with IE below one year of age, 25 cases were enrolled in the sodium hyaluronate (SH) group to receive 2.5 U BoNT-A injection combined with SH in each medial rectus muscle (MR). Thirty patients were enrolled in the control group to receive 2.5 U BoNT-A injection with normal saline in each MR. The change in mean primary ocular deviation (POD) and complications were assessed at 2 weeks, 1 month, 3 months, and 6 months post injection. Mann-Whitney U test was used for non-parametric unpaired data. Chi-square test and Fisher's exact test were used to test for the strength of the association between the two categorical variables., Results: Satisfactory ocular alignment was achieved in 76% in SH group and 73% in the control group (P value = 0.80). While the change in mean POD was comparable (29.2 prism diopters [PD] vs 29.3 PD; P value = 0.65), the complication rates were significantly lesser in SH (16% vs 33.3%; P value = 0.14)., Conclusion: BoNT-A combined with SH is equally effective with lesser complications as compared to botulinum toxin alone in the treatment of IE., Competing Interests: None

Purpose: COVID-19 related pan- India lockdown brought teleophthalmology to the forefront. The study ventures to understand the relevance of this modality in a government setup. The objective is to understand the feasibility, clinical profile and addressability of patients using teleconsultation in ophthalmology at a tertiary care government medical university during the COVID-19 Lockdown in India., Methods: An online survey targeting faculty members and resident doctors in a tertiary eye center in a government medical university in north India was conducted. Various aspects of teleconsultation were analyzed including the number and preferential mode of consultations, commonest complaints and diagnoses made. Frequency and factors mandating physical examination of patients was also analyzed., Results: The questionnaire was sent to 40 ophthalmologists of whom 38 responded. A total of 4880 teleconsultations were given. The commonest mode of communication was by WhatsApp messages (65.6%) and E-mail was the least preferred medium. More than 80% consultations were from previously seen patients. Red eye was the commonest presenting complaint (22.8%), followed by watering (18.7%) and foreign body sensation (14.5%). Computer vision syndrome was the commonest diagnosis (25.9%) followed by conjunctivitis (17.7%) and refractive error (17.7%). About 40% required physical examination, mostly due to uncertain diagnosis (22%) or inadequate response to prescribed treatment (19%)., Conclusion: Teleconsultation was feasible in a government medical university for providing ophthalmic services during lockdown. WhatsApp was the preferred communication modality, computer vision syndrome was the most frequent tentative diagnosis and approximately 60% did not require in-person physical examination., Competing Interests: None

Cancer is the manifestation of uncontrolled cellular growth and immune escape mechanisms. Unrestrained tumor growth can be associated with incidental errors in the genome during replication and genotoxic agents can alter the structure and sequence of our DNA. Among all genetic aberrations in cancer, only limited number of mutations can produce immunogenic antigens which have the potential to bind human leukocyte antigen class I or human leukocyte antigen class II, and help activate the adaptive immune system. These neoantigens can be recognized by CD8 + and CD4 + neoantigen-specific T lymphocytes. Recently, several immune checkpoint targeting drugs have been approved for clinical use. Primarily, these drugs expand and facilitate the cytotoxic activity of neoantigen-specific T cells to eradicate tumors. Differential drug response across cancers could be attributed, at least in part, to differences in the 'tumor antigen landscape' and 'antigen presentation pathway' in patients. Although tumor mutational burden correlates with response to immune checkpoint inhibitors in many cancer types and has evolved as a broad biomarker, a comprehensive understanding of the neoantigen landscape and the function of cognate T cell responses is lacking and is needed for improved patient selection criteria and neoantigen vaccine design. Here, we review cancer neoantigens, their implications for antitumor responses, the dynamics of neoantigen-specific T cells, and the advancement of neoantigen-based therapy in proposed clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Herpes Zoster is a neuro-cutaneous disorder caused by reactivation of Varicella-Zoster Virus. A number of factors such as old age, psychological stress, low immune states, radiation exposure and physical trauma have been implicated for reactivation. Post traumatic herpes zoster involving maxillary and ophthalmic division of trigeminal nerve is very rare and has been reported in presence of Immune deficiency and following iatrogenic trauma (nerve block injection). We report a unique presentation of simultaneous ophthalmic and maxillary herpes zoster following a facial injury with a wooden stick in an immune-competent female., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Oman Ophthalmic Society.)

Purpose: To validate the smartphone photography as a screening tool for amblyogenic conditions in children., Methods: Children between 5 to 8 years attending eye out patient department (OPD) were photographed (by an optometrist) with a smartphone to capture their pupillary red reflexes followed by clinical examination by the principal investigator (PI). The PI on the basis of clinical examination identified children with significant amblyogenic conditions and, subsequently, two ophthalmologists independently categorized the photographs on the basis of color, symmetry, and shape of the pupillary reflex into normal or abnormal. The identification of amblyogenic conditions on clinical examination was compared to that on photography. Refractive errors <3D and anisometropia <2D were excluded. Sensitivity, specificity, positive predictive value, and negative predictive value of smartphone photography screening were determined., Results: In all, 250 children were screened. Clinically 23.6% were harboring amblyogenic conditions. The mean sensitivity and specificity of screening by smartphone were 94% and 91%, respectively., Conclusion: Smartphone photography is a reliable tool for detection of amblyogenic conditions in children., Competing Interests: There are no conflicts of interest.

Background: Trachoma is the world's leading infectious cause of blindness. In 1996, WHO launched the Alliance for the Global Elimination of Trachoma by the year 2020, based on the 'SAFE' strategy (surgery, antibiotics, facial cleanliness, and environmental improvement)., Objectives: To assess the evidence supporting the antibiotic arm of the SAFE strategy by assessing the effects of antibiotics on both active trachoma (primary objective), Chlamydia trachomatis infection of the conjunctiva, antibiotic resistance, and adverse effects (secondary objectives)., Search Methods: We searched relevant electronic databases and trials registers. The date of the last search was 4 January 2019., Selection Criteria: We included randomised controlled trials (RCTs) that satisfied either of two criteria: (a) trials in which topical or oral administration of an antibiotic was compared to placebo or no treatment in people or communities with trachoma, (b) trials in which a topical antibiotic was compared with an oral antibiotic in people or communities with trachoma. We also included studies addressing different dosing strategies in the population.  DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach., Main Results: We identified 14 studies where individuals with trachoma were randomised and 12 cluster-randomised studies. Any antibiotic versus control (individuals)Nine studies (1961 participants) randomised individuals with trachoma to antibiotic or control (no treatment or placebo). All of these studies enrolled children and young people with active trachoma. The antibiotics used in these studies included topical (oxy)tetracycline (5 studies), doxycycline (2 studies), and sulfonamides (4 studies). Four studies had more than two study arms. In general these studies were poorly reported, and it was difficult to judge risk of bias.These studies provided low-certainty evidence that people with active trachoma treated with antibiotics experienced a reduction in active trachoma at three months (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69 to 0.89; 1961 people; 9 RCTs; I 2 = 73%) and 12 months (RR 0.74, 95% CI 0.55 to 1.00; 1035 people; 4 RCTs; I 2 = 90%). Low-certainty evidence was available for ocular infection at three months (RR 0.81, 95% CI 0.63 to 1.04; 297 people; 4 RCTs; I 2 = 0%) and 12 months (RR 0.25, 95% CI 0.08 to 0.78; 129 people; 1 RCT). None of these studies assessed antimicrobial resistance. In those studies that reported harms, no serious adverse effects were reported (low-certainty evidence).Oral versus topical antibiotics (individuals)Eight studies (1583 participants) compared oral and topical antibiotics. Only one study included people older than 21 years of age. Oral antibiotics included azithromycin (5 studies), sulfonamides (2 studies), and doxycycline (1 study). Topical antibiotics included (oxy)tetracycline (6 studies), azithromycin (1 study), and sulfonamide (1 study). These studies were poorly reported, and it was difficult to judge risk of bias.There was low-certainty evidence of little or no difference in effect between oral and topical antibiotics on active trachoma at three months (RR 0.97, 95% CI 0.81 to 1.16; 953 people; 6 RCTs; I 2 = 63%) and 12 months (RR 0.93, 95% CI 0.75 to 1.15; 886 people; 5 RCTs; I 2 = 56%). There was very low-certainty evidence for ocular infection at three or 12 months. Antimicrobial resistance was not assessed. In those studies that reported adverse effects, no serious adverse effects were reported; one study reported abdominal pain with azithromycin; one study reported a couple of cases of nausea with azithromycin; and one study reported three cases of reaction to sulfonamides (low-certainty evidence).Oral azithromycin versus control (communities)Four cluster-randomised studies compared antibiotic with no or delayed treatment. Data were available on active trachoma at 12 months from two studies but could not be pooled because of reporting differences. One study at low risk of bias found a reduced prevalence of active trachoma 12 months after a single dose of azithromycin in communities with a high prevalence of infection (RR 0.58, 95% CI 0.52 to 0.65; 1247 people). The other, lower quality, study in low-prevalence communities reported similar median prevalences of infection at 12 months: 9.3% in communities treated with azithromycin and 8.2% in untreated communities. We judged this moderate-certainty evidence for a reduction in active trachoma with treatment, downgrading one level for inconsistency between the two studies. Two studies reported ocular infection at 12 months and data could be pooled. There was a reduction in ocular infection (RR 0.36, 0.31 to 0.43; 2139 people) 12 months after mass treatment with a single dose compared with no treatment (moderate-certainty evidence). There was high-certainty evidence of an increased risk of resistance of Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli to azithromycin, tetracycline, and clindamycin in communities treated with azithromycin, with approximately 5-fold risk ratios at 12 months. The evidence did not support increased resistance to penicillin or trimethoprim-sulfamethoxazole. None of the studies measured resistance to C trachomatis. No serious adverse events were reported. The main adverse effect noted for azithromycin (˜10%) was abdominal pain, vomiting, and nausea.Oral azithromycin versus topical tetracycline (communities)Three cluster-randomised studies compared oral azithromycin with topical tetracycline. The evidence was inconsistent for active trachoma and ocular infection at three and 12 months (low-certainty evidence) and was not pooled due to considerable heterogeneity. Antimicrobial resistance and adverse effects were not reported.Different dosing strategiesSix studies compared different strategies for dosing. There were: mass treatment at different dosing intervals; applying cessation or stopping rules to mass treatment; strategies to increase mass treatment coverage. There was no strong evidence to support any variation in the recommended annual mass treatment., Authors' Conclusions: Antibiotic treatment may reduce the risk of active trachoma and ocular infection in people infected with C trachomatis, compared to no treatment/placebo, but the size of the treatment effect in individuals is uncertain. Mass antibiotic treatment with single dose oral azithromycin reduces the prevalence of active trachoma and ocular infection in communities. There is no strong evidence to support any variation in the recommended periodicity of annual mass treatment. There is evidence of an increased risk of antibiotic resistance at 12 months in communities treated with antibiotics.

Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.

Objectives: The intracellular DNA sensor stimulator of interferon genes (STING) has recently been shown to play a vital role in anti-viral and anti-tumor immune responses stimulating cytokine production. While human papillomavirus (HPV) is a causative agent for a subset of head and neck squamous cell carcinoma (HNSCC) with unique etiology and clinical outcome, how the STING pathway is regulated in a virus-induced tumor microenvironment is not well understood. Since STING inactivation likely reflects immunoescape via innate immunity, we hypothesized that its restoration would improve efficacy of the immune modulatory monoclonal antibody (mAb), cetuximab., Materials and Methods: We correlated STING protein expression with clinical parameters by immunohistochemistry (n = 106) and its mRNA expression from The Cancer Genome Atlas (TCGA) in HNSCC tissue specimens. STING protein expression was tested for association with cancer-specific survival (CSS). We further examined the impact of STING activation on cetuximab-mediated immunity using an in vitro NK:DC:tumor cells co-culture system., Results: In this study, we found that expression of STING both at the protein and mRNA level was higher in HPV positive (HPV + ) specimens but unrelated to TNM stage or cancer-specific survival. Our in vitro studies verified that STING activation enhanced cetuximab mediated NK cell activation and DC maturation., Conclusion: Our findings suggest a novel role of STING in HPV-related carcinogenesis, in which activation of the STING signaling pathway may facilitate anti-tumor response in HNSCC patients, particularly in combination with therapeutic monoclonal antibodies (mAbs) such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory TLR8 agonist to cetuximab therapy might result in enhanced T-lymphocyte stimulation and anti-EGFR-specific priming. Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3 to 4 weekly doses of motolimod (2.5 mg/m 2 ) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells. Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed myeloid-derived suppressor cell (MDSC) suppression of T-cell proliferation in vitro These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in tumor-infiltrating lymphocytes. Motolimod plus cetuximab also decreased induction of Treg and reduced markers of suppression, including CTLA-4, CD73, and membrane-bound TGFβ. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8 + T-cell infiltration into tumors. These T cells manifested increased T-cell receptor (TCR) clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT. Conclusions: Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC. Clin Cancer Res; 24(1); 62-72. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1 + TIL has been reported in human papillomavirus (HPV) + HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1 high T cells may be more exhausted than PD-1 low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1 + TIL was higher in HPV + patients ( P = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1 high CD8 + TILs were more frequent in HPV - patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1 high CD8 + TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence ( P < 0.001), while higher fractions of PD-1 low T cells associated with HPV positivity and better outcome. In a murine HPV + HNC model, anti-PD-1 mAb therapy differentially modulated PD-1 high/low populations, and tumor rejection associated with loss of dysfunctional PD-1 high CD8 + T cells and a significant increase in PD-1 low TIL. Thus, the extent of PD-1 expression on CD8 + TIL provides a potential biomarker for anti-PD-1-based immunotherapy. Cancer Res; 77(22); 6353-64. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Survival benefit and long-term duration of clinical response have been seen using the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody (mAb) nimotuzumab. Blocking EGFR signaling may not be the only mechanism of action underlying its efficacy. As an IgG1 isotype mAb, nimotuzumab's capacity of killing tumor cells by antibody dependent cellular cytotoxicity (ADCC) and to induce an immune response in cancer patients have not been studied. ADCC-induced by nimotuzumab was determined using a 51 Cr release assay. The in vitro effect of nimotuzumab on natural killer (NK) cell activation and dendritic cell (DC) maturation and the in vivo frequency of circulating regulatory T cells (Tregs) and NK cells were assessed by flow cytometry. Cytokine levels in supernatants were determined by ELISA. ELISpot was carried out to quantify EGFR-specific T cells in nimotuzumab-treated head and neck cancer (HNSCC) patients. Nimotuzumab was able to kill EGFR+ tumor cells by NK cell-mediated ADCC. Nimotuzumab-activated NK cells promoted DC maturation and EGFR-specific CD8+ T cell priming. Interestingly, nimotuzumab led to upregulation of some immune checkpoint molecules on NK cells (TIM-3) and DC (PD-L1), to a lower extent than another EGFR mAb, cetuximab. Furthermore, circulating EGFR-specific T cells were identified in nimotuzumab-treated HNSCC patients. Notably, nimotuzumab combined with cisplatin-based chemotherapy and radiation increased the frequency of peripheral CD4+CD39+FOXP3+Tregs which otherwise were decreased to baseline values when nimotuzumab was used as monotherapy. The frequency of circulating NK cells remained constant during treatment. Nimotuzumab-induced, NK cell-mediated DC priming led to induction of anti-EGFR specific T cells in HNSCC patients. The association between EGFR-specific T cells and patient clinical benefit with nimotuzumab treatment should be investigated.

Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD-L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma). Tumors were established in two locations per mouse (neck and flank), and fractionated RT (2 Gy × 4 or 2 Gy × 10) was delivered only to the neck tumor, alone or during anti-PD-1 mAb immunotherapy. PD-L1 expression was measured by PET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and results were validated by flow cytometry. PET/CT imaging demonstrated significantly increased tracer uptake in irradiated neck tumors compared with non-irradiated flank tumors. Ex vivo analysis by biodistribution and flow cytometry validated PD-L1 upregulation specifically in irradiated tumors. In the HNSCC model, RT-induced PD-L1 upregulation was only observed after 2 Gy × 10 fractionated RT, while in the B16F10 model upregulation of PD-L1 occurred after 2 Gy × 4 fractionated RT. Fractionated RT, but not anti-PD-1 therapy, upregulated PD-L1 expression on tumor and infiltrating inflammatory cells in murine models, which could be non-invasively monitored by immunoPET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and differentially identified anti-PD-1 responsive as well as selectively irradiated tumors in vivo .

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8 + tumor-infiltrating lymphocytes (TIL) and compared them with those of peripheral blood T lymphocytes (PBL) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8 + TILs compared with CD8 + PBLs ( P = 0.008 and P = 0.02, respectively). This increased CD8 + TIL population coexpressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8 + TILs. Indeed, the increased frequency of PD-1 + and TIM-3 + CD8 + TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8 + T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8 + TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. Cancer Immunol Res; 5(5); 408-16. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background and Aim: The prosthetic options for higher level amputees are limited and costly. Advancements in computer-aided design programs and three-dimensional printing offer the possibility of designing and manufacturing transitional prostheses at very low cost. The aim of this project was to describe an inexpensive three-dimensional printed mechanical shoulder prosthesis to assist a pre-selected subject in performing bi-manual activities., Technique: The main function of the body-powered, manually adjusted three-dimensional printed shoulder prosthesis is to provide a cost-effective, highly customized transitional device to individuals with congenital or acquired forequarter amputations., Discussion: After testing the prototype on a young research participant, a partial correction of the patient's spinal deviation was noted due to the counterweight of the device. The patient's family also reported improved balance and performance of some bimanual activities after 2 weeks of using the device. Limitations of the design include low grip strength and low durability. Clinical relevance The prosthetic options for higher level amputees are limited and costly. The low-cost three-dimensional printed shoulder prosthesis described in this study can be used as a transitional device in preparation for a more sophisticated shoulder prosthesis.

Purpose: Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity., Experimental Design: CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells., Results: CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab., Conclusions: These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707-16. ©2016 AACR., Competing Interests: Robert L. Ferris has received research grants from Bristol Myers Squibb and AZ/Medimmune and has been a consultant/advisory board member for Celgene, Merck, BMS and AZ/Medimmune., (©2016 American Association for Cancer Research.)