eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer.

Cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T cells, allowing tumors to suppress T cell activity. Clinical trials utilizing antibodies that disrupt the PD-1/PD-L1 checkpoint have yielded remarkable results, with anti-PD-1 immunotherapy approved as first-line therapy for lung cancer patients. We used CRISPR-based screening to identify regulators of PD-L1 in human lung cancer cells, revealing potent induction of PD-L1 upon disruption of heme biosynthesis. Impairment of heme production activates the integrated stress response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5' UTR, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We demonstrated that ISR-dependent PD-L1 translation requires the translation initiation factor eIF5B. eIF5B overexpression, which is frequent in lung adenocarcinomas and associated with poor prognosis, is sufficient to induce PD-L1. These findings illuminate mechanisms of immune checkpoint activation and identify targets for therapeutic intervention.

Successful Ponseti-treated Clubfeet at Age 2 Years: What Is the Rate of Surgical Intervention After This?

BACKGROUND: In recent decades, nonoperative Ponseti casting has become the standard of care in the treatment of idiopathic clubfoot. However, the rate of recurrence, even after successful Ponseti treatment is not insignificant. The purpose of this study was to determine the future rate, timing, and type of surgery needed in patients whose idiopathic clubfeet treated by Ponseti casting were considered successful at the age of 2 years. METHODS: Inclusion criteria for this retrospective study were patients under 3 months with idiopathic clubfoot treated exclusively by Ponseti casting, who had successful outcomes at 2 years of age without surgery, and who had at least 5 years of follow-up. The total number of surgical interventions in the age range 2 to 5 and above 5 years, the number and type of procedures performed, and the timing of surgery were reviewed. RESULTS: Three hundred thirty-six patients with a total of 504 clubfeet fulfilled the inclusion criteria. One hundred twenty-two of these 336 patients (36.3%) eventually underwent surgical intervention. Between 2 and 5 years of age, 79 patients (23.5%) with 104 feet (20.6%) underwent surgery. The most common procedures performed between 2 and 5 years were limited (a la carte) in scope: tibialis anterior tendon transfer, posterior release, plantar fascia release, and repeat tendo-Achilles lengthening. At age above 5 years, 53 patients (20.1%) with 65 feet (16.9%) underwent surgery. Ten of these 53 patients had already undergone surgery between 2 and 5 years of age. The procedures most commonly performed were similar. CONCLUSIONS: In patients with idiopathic clubfoot who reached 2 years of age with successful outcomes from Ponseti cast treatment, ∼35% eventually underwent surgical intervention, mostly limited (a la carte), to regain or maintain a plantigrade foot. The most commonly performed procedures include tibialis anterior tendon transfer, posterior capsular release, plantar fascia release and repeat tendo-Achilles lengthening, either in isolation or in combination. However, before considering surgery, the need for these procedures can, and should, be minimized by recasting recurrent deformities using Ponseti method. LEVEL OF EVIDENCE: Level III.

Timing, Sites, and Correlates of Lung Cancer Recurrence.

INTRODUCTION: Understanding temporal and anatomic patterns of lung cancer recurrence could guide disease management and monitoring. However, these data are not available in population-based datasets and are not routinely recorded in clinical trials. MATERIALS AND METHODS: We identified cases of stage 1 to 3 lung cancer diagnosed January 1, 2000, to December 31, 2017, in the tumor registry of a National Cancer Institute-designated comprehensive cancer center. For cases with documented disease recurrence, we recorded anatomic site(s) and timing. We estimated time to recurrence using Kaplan-Meier methods. Associations between case characteristics and recurrence features were assessed using univariable and multivariable logistic regression models and Cox regression models. RESULTS: A total of 1619 cases of stage 1 to 3 lung cancer from 1549 patients were included in the analysis. Of these, 466 (30%) patients developed recurrent lung cancer. The most common type of first recurrence was distant disease, most commonly central nervous system (CNS) (37%). In multivariable analyses, race (P = .02) and primary treatment modality (P < .001) correlated with recurrent disease, whereas tumor histology (P = .004) and primary treatment modality (P < .001) were associated specifically with distant recurrence. Patient age (P = .05) and initial TNM stage (P = .001) correlated with timing of recurrence. CONCLUSION: In this single-center series of stage 1 to 3 lung cancer, recurrent disease was associated with race, histology, and treatment modality, and most commonly occurred in the CNS. Modulation of clinical and radiographic disease monitoring according to recurrence risk, timing, and site may offer a means to identify future lung cancer when it remains asymptomatic and highly treatable.

Objective Measurement of Brace Wear in Successfully Ponseti-Treated Clubfeet: Pattern of Decreasing Use in the First 2 Years.

PURPOSE: Once Ponseti correction of a clubfoot is achieved and 3-month full-time bracing treatment is completed, part-time bracing treatment for 12 hours at night for 2 to 4 years is considered necessary to maintain a successful outcome. This study objectively documents the amount of daily orthosis wear time in those who maintained correction at age 2 years and, in so doing, determines how well patients' caretakers comply with the prescribed brace program. METHODS: Patients <3 months old with idiopathic clubfeet when Ponseti treatment was initiated, who successfully maintained correction at age 2 years without surgery and who had complete objective brace wear data, were included. The foot abduction orthoses had a temperature data logger embedded in a shoe. Six 3-month time intervals were monitored in every patient as follows: full time: 0 to 3; night time: 4 to 6, 7 to 9, 10 to 12, 13 to 15, and 16 to 18 months. The families were not informed that hours of brace wear were being measured. RESULTS: One hundred twenty-four patients with 187 clubfeet were included. During the 0- to 3-month interval, wear time averaged 19.8 hr/d. After this period of full-time use, the night-time brace wear decreased over each of the subsequent five intervals: 11.9, 9.6, 8.6, 7.9, and 7.7 hours. By the 18-month period of brace wear, 1 of 3 patients wore the orthoses less than 6 hours per day, and nearly 1 of 2 patients wore the orthoses less than 8 hours per day. DISCUSSION: In patients evaluated at age 2 years whose clubfeet had successful nonsurgical treatment, night-time brace wear varied greatly and decreased over each 3-month period measured. By the second year of bracing treatment, nearly half of the patients wore them 8 hours or less. LEVEL OF EVIDENCE: Level IV case series.

Correction: Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.

[This corrects the article DOI: 10.1371/journal.pgen.1007168.].

Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.

Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita.