Oncolytic α-herpesvirus and myeloid-tropic cytomegalovirus cooperatively enhance systemic antitumor responses.

Oncolytic virotherapy aims to activate host antitumor immunity. In responsive tumors, intratumorally injected herpes simplex viruses (HSVs) have been shown to lyse tumor cells, resulting in local inflammation, enhanced tumor antigen presentation, and boosting of antitumor cytotoxic lymphocytes. In contrast to HSV, cytomegalovirus (CMV) is nonlytic and reprograms infected myeloid cells, limiting their antigen-presenting functions and protecting them from recognition by natural killer (NK) cells. Here, we show that when co-injected into mouse tumors with an oncolytic HSV, mouse CMV (mCMV) preferentially targeted tumor-associated myeloid cells, promoted the local release of proinflammatory cytokines, and enhanced systemic antitumor immune responses, leading to superior control of both injected and distant contralateral tumors. Deletion of mCMV genes m06, which degrades major histocompatibility complex class I (MHC class I), or m144, a viral MHC class I homolog that inhibits NK activation, was shown to diminish the antitumor activity of the HSV/mCMV combination. However, an mCMV recombinant lacking the m04 gene, which escorts MHC class I to the cell surface, showed superior HSV adjuvanticity. CMV is a potentially promising agent with which to reshape and enhance antitumor immune responses following oncolytic HSV therapy.

A Retrospective Longitudinal Study of 460 Patients with ABCA4-Associated Retinal Disease.

PURPOSE: To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution. DESIGN: Retrospective, single-institution cohort review. PARTICIPANTS: Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4. METHODS: DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects. MAIN OUTCOME MEASURES: Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field. RESULTS: A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4-76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual. CONCLUSIONS: ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium-based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients' clinical findings in most cases will be more useful for predicting their clinical course than their genotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Physical durability: are bed nets getting any stronger?

BACKGROUND: For at least a decade, concerns have been raised about the physical durability of insecticide-treated nets (ITNs) and their ability to remain in good condition for at least three years. To discover if the resistance to damage (RD) of ITNs has improved or not, the RD scores of ITNs sampled in 2013 and 2020 were compared. METHODS: The RD scores and disaggregated textile performance data for nine ITNs recommended by the WHO pesticide evaluation scheme (WHOPES) measured in 2013 were compared with WHO-prequalified ITNs sampled in 2020. This included assessment of newer ITNs not available in 2013, to determine the extent to which product development has led to performance improvements across all available ITNs in the intervening years. RESULTS: The resistance to damage of ITNs has not generally improved from 2013 to 2020, and in some cases performance is worse. The average RD score of comparable ITNs brands decreased from 40 in 2013 to 36 in 2020. Of the nets available in 2020, only two of the twenty-four ITN products tested achieved an RD score of > 50, while six ITNs had very low RD scores of < 30, highlighting a serious inherent, and literal weakness in many WHO-prequalified ITNs. CONCLUSIONS: The long-term physical durability of ITN products cannot be expected to improve while their resistance to damage remains so low, and major upgrades to the performance standards of textile materials used to make ITNs, as well as incentives to develop stronger ones are urgently required.

Smoking cessation among sexual minority women: Differences in cigarette quit ratios across age, race/ethnicity, and sexual orientation.

OBJECTIVE: Sexual minority (SM) women experience tobacco-related disparities and report a higher prevalence of cigarette use, as well as subgroup differences in use, but little is known about their quitting behavior. This study used data from a national sample of United States SM women to examine cigarette quit ratios overall and by age, race/ethnicity, and sexual orientation. METHODS: Using baseline survey data from the Generations Study (2016-2017, N = 812), we calculated quit ratios among SM women reporting lifetime smoking (100+ cigarettes) who reported currently smoking "not at all" relative to those reporting smoking "every day or some days." Quitting was compared across cohort, race/ethnicity, and sexual orientation, controlling for household income. RESULTS: SM women reporting lifetime smoking in the older cohort were significantly more likely to report quitting than those in the younger cohort. Bisexual women also reported a greater likelihood of quitting than gay/lesbian women. There was no association between race/ethnicity and the probability of quitting smoking. CONCLUSIONS: SM women remain a priority for tobacco prevention and cessation efforts. There is evidence that the probability of quitting cigarettes differs across sexual orientation and age cohorts, which has implications for tailoring of interventions and tobacco communications.

MENISCUS MICROPYON: An Ophthalmoscopic Sign Possibly Associated With Epiretinal Proliferation After Retinal Surgery With Gas Tamponade.

PURPOSE: To describe an ophthalmoscopic sign, termed a meniscus micropyon, and its possible association with proliferative vitreoretinopathy/epiretinal membrane (ERM) formation after retinal surgery with gas tamponade. METHODS: Patients with intravitreal gas were examined postoperatively by one of six vitreoretinal surgeons from four institutions. A micropyon was defined as a white-yellow, solid-appearing consolidation along the meniscus (i.e., the fluid-gas interface). RESULTS: A micropyon was visualized and photographed in 49 patients who received intravitreal gas. Preoperatively, retinal breaks were present in all 49 eyes and rhegmatogenous retinal detachment in 45 (92%). Postoperatively, 39 eyes (80%) developed epiretinal proliferation: 16 eyes (33%) developed recurrent rhegmatogenous retinal detachment from proliferative vitreoretinopathy, 6 eyes (12%) re-detached without frank proliferative vitreoretinopathy, 9 eyes (18%) developed postoperative ERM/worsening, and 8 eyes (16%) had postoperative ERM but no preoperative optical coherence tomography to determine if the postoperative ERM was new or worsening. The single-operation anatomical success in eyes with a micropyon was 51%, which was lower than that of a contemporaneous rhegmatogenous retinal detachment control group (91%) in which no micropyon was detected. In two patients, micropyons were biopsied during pars plana vitrectomy and examined histopathologically; they consist predominantly of white blood cells. CONCLUSION: The meniscus micropyon is an ophthalmoscopic sign that can occur after retinal surgery with gas tamponade. Features that distinguish a micropyon from postvitrectomy fibrin/fibrinoid syndrome include delayed appearance, hyperautofluorescence, absence of translucent strands or sheets in the anterior chamber or vitreous cavity, and the histopathologic identification of white blood cells. A clinically detectable micropyon may be a biomarker of proliferative vitreoretinopathy/ERM formation.

Geographical Variation in the Associations Between School Characteristics and Homophobic Bullying: a Contextual Analysis.

Homophobic bullying constitutes a serious threat to adolescent well-being and could be understood as an ecological phenomenon, influenced by diverse school, regional, and community contexts. This study examined geographic variations in the relationship between school characteristics and homophobic bullying. Data from 2244 California schools, including student surveys and administrative records, were combined and analyzed using geographically weighted regression (GWR). Results showed that the associations between school characteristics and general victimization were consistent across geographic areas. However, when it came to homophobic bullying, the relationships with school characteristics varied significantly based on location. Notably, regions with high intolerance, urbanity, large school size, and small student-teacher ratios appeared to offer protection against bullying. Additionally, student socioeconomic status influenced bullying in disadvantaged rural schools with limited Gay-Straight Alliance (GSA) presence. Ethnic diversity also played a role, with low diversity or dominance of two ethnic groups linked to higher bullying rates.

Revisiting the Latin vocabulary of Terminologia Histologica: I. Nouns.

Almost 20% of the Latin nouns (193/993) in Terminologia Histologica (TH), the international standard nomenclature for human histology and cytology, display linguistic problems, particularly in the areas of orthography, gender, and declension. Some anatomists have opposed efforts to restore the quality of the Latin nomenclature as pedantry, preferring to create or modify Latin words so that they resemble words in English and other modern languages. A Latin microanatomical nomenclature is vulnerable to the criticism of anachronism, so the requirement for the use of authentic Latin, including derivation of new words from Greek and Latin words rather than from modern languages, if possible, may be even greater than it is for the anatomical nomenclature. The most common problem identified here appears to have been caused by derivation of Latin nouns by addition of -us and -um second declension endings to English words. Many Latin nouns (128) in TH contain one of six morphemes that have been treated this way even though the original Greek words are either first declension masculine or third declension neuter nouns. Ironically, deriving Latin nouns directly from Greek morphemes often results in words that look more familiar to speakers of Romance and Germanic languages than those derived indirectly through modern languages (e.g., astrocyte, collagene, dendrita, lipochroma, osteoclasta and telomere instead of astrocytus, collagenum, dendritum, lipochromum, osteoclastus, and telomerus).

The Developmental Collision Hypothesis: An Empirical Test With Three Generations of Sexual Minority Youth.

Sexual minority youth experience disproportionate rates of mental health symptomatology relative to their heterosexual peers. Less is known about why these disparities have persisted despite growing public awareness of sexual diversity. The developmental collision hypothesis states that increased cultural visibility of sexual diversity has accelerated the developmental timing of sexual minority identity formation processes such that they collide with early adolescence, a uniquely sensitive period for experiencing identity-based stigma and associated mental health vulnerability. To test this hypothesis, levels and relations between ages of sexual minority identity development milestones, frequency of LGBT-related victimization, and depressive symptoms were examined across three age-matched but cohort-distinct samples of sexual minority adolescents. Data come from three secondary datasets of sexual minority youth who were adolescents in the 1990s, 2000s, and 2010s, respectively: the Challenges and Coping Study, the Victimization and Mental Health among High Risk Youths Study, and the Risk and Protective Factors for Suicide among Sexual Minority Youth Study (n = 1312; Mage = 17.34, SD = 1.30; 52% female). Adolescents from more recent cohorts reported earlier mean ages of several milestones but similar frequencies of LGBT-related victimization relative to those from less recent cohorts. Path analysis models showed that earlier milestones were associated indirectly with more depressive symptoms through LGBT-related victimization. Notably, earlier ages of self-identification and disclosure of a sexual minority identity were also directly related to less depressive symptoms. Few generational differences in relations between constructs emerged. Findings garner initial support for the developmental collision hypothesis and suggest that LGBT-related victimization, rather than earlier milestones themselves, increases mental health vulnerability.

The long-lasting enigma of polycytidine (polyC) tract.

Long polycytidine (polyC) tracts varying in length from 50 to 400 nucleotides were first described in the 5'-noncoding region (NCR) of genomes of picornaviruses belonging to the Cardio- and Aphthovirus genera over 50 years ago, but the molecular basis of their function is still unknown. Truncation or complete deletion of the polyC tracts in picornaviruses compromises virulence and pathogenicity but do not affect replicative fitness in vitro, suggesting a role as "viral security" RNA element. The evidence available suggests that the presence of a long polyC tract is required for replication in immune cells, which impacts viral distribution and targeting, and, consequently, pathogenic progression. Viral attenuation achieved by reduction of the polyC tract length has been successfully used for vaccine strategies. Further elucidation of the role of the polyC tract in viral replication cycle and its connection with replication in immune cells has the potential to expand the arsenal of tools in the fight against cancer in oncolytic virotherapy (OV). Here, we review the published data on the biological significance and mechanisms of action of the polyC tract in viral pathogenesis in Cardio- and Aphthoviruses.

MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum.

The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified vaccine MeV strain that exhibits oncolytic properties and escapes antimeasles antibodies in vivo. We engineered this virus using homologous envelope glycoproteins from the closely-related but serologically non-cross reactive canine distemper virus (CDV). By fusing a high-affinity CD46 specific single-chain antibody fragment (scFv) to the CDV-Hemagglutinin (H), ablating its tropism for human nectin-4 and modifying the CDV-Fusion (F) signal peptide we achieved efficient retargeting to CD46. A receptor binding affinity of ~20 nM was required to trigger CD46-dependent intercellular fusion at levels comparable to the original MeV H/F complex and to achieve similar antitumor efficacy in myeloma and ovarian tumor-bearing mice models. In mice passively immunized with measles-immune serum, treatment of ovarian tumors with MeV-Stealth significantly increased overall survival compared with treatment with vaccine-lineage MeV. Our results show that MeV-Stealth effectively targets and lyses CD46-expressing cancer cells in mouse models of ovarian cancer and myeloma, and evades inhibition by human measles-immune serum. MeV-Stealth could therefore represent a strong alternative to current oncolytic MeV strains for treatment of measles-immune cancer patients.