PURPOSE: Asthma is a complex disease caused by interplay of genes and environment on the genome of an individual. Copy number variations (CNVs) are more common compared to the other variations that disrupt genome organization. The effect of CNVs on asthma subgenome has been less studied compared to studies on the other variations. We report the assessments of CNV burden in asthma genes of normal cohorts carried out in different geographical areas of the world and discuss the relevance of the observation with respect to asthma pathogenesis. METHODS: CNV analysis was performed using Affymerix high-resolution arrays, and various bioinformatics tools were used to understand the influence of genes on asthma pathogenesis. RESULTS: This study identified 61 genes associated with asthma and provided various mechanisms and pathways underlying asthma pathogenesis. CCL3L1, ADAM8, and MUC5B were the most prevalent asthma genes. Among them, CCL3L1 was found across all 12 populations in varying copy number states. This study also identified the inheritance of asthma-CNVs from parents to offspring creating the latent period for manifestation of asthma. CONCLUSIONS: This study revealed CNV burden with varying copy number states and identified susceptibility towards the disease manifestation. It can be hypothesized that primary CNVs may not be the initiating event in the pathogenesis of asthma and additional preceding mutations or CNVs may be required. The initiator or primary CNVs sensitize normal cohorts leading to an increased probability of accumulating mutations or exposure to allergic stimulating agents that can augment the development of asthma.
Asthma* ; Cohort Studies* ; Computational Biology ; DNA Copy Number Variations ; Genetic Markers ; Genome ; Humans ; Inheritance Patterns ; Parents ; Wills

STUDY DESIGN: Observational retrospective computed tomography (CT) based study. PURPOSE: To analyze the congenital anomalies of the cervical spine, their morphological variations and their clinical significance. OVERVIEW OF LITERATURE: Studies published to date have focused mainly on upper cervical anomalies; no study has comprehensively reported on anomalies of both the occipitocervical and subaxial cervical spine. METHODS: Nine hundred and thirty cervical spine CT scans performed in Ganga Hospital, Coimbatore, India between January 2014 and November 2017 were screened by two independent observers to document anomalies of both the upper and lower cervical spine. CT scans conducted for infection, tumor, and/or deformity were excluded. Different morphological variations, embryological basis, and clinical significance of the anomalies were discussed. RESULTS: Of the 930 CT scans screened, 308 (33.1%) had congenital anomaly. Of these, 184 (59.7%) were males and 124 (40.2.7%) were females, with a mean age of 44.2 years (range, 14–78 years). A total of 377 anomalies were identified, with 69 cases (7.4%) having more than one anomaly. Two hundred and fifty (26.8%) anomalies of the upper cervical region (occiput to C2–C3 disk space) were identified, with the most common upper cervical anomalies being high-riding vertebral artery (108 cases, 11.6%) and ponticulus posticus (PP) (75 cases, 8%). One hundred and twenty seven (13.6%) anomalies of the lower cervical spine (C3–C7) were noted, of which double foramen transversarium was the most common anomaly observed in 46 cases (4.8%). CONCLUSIONS: We found that 33.1% of CT scans had at least one congenital anomaly. Some anomalies, such as abnormal facet complex and arch anomalies, have to be differentiated from fractures in a trauma patient. Other anomalies, like PP, have to be looked for during preoperative planning to avoid complications during surgery. Therefore, knowledge of these anomalies is important as different anomalies have different clinical courses and management.
Congenital Abnormalities ; Female ; Humans ; India ; Male ; Retrospective Studies ; Spine ; Tomography, X-Ray Computed ; Vertebral Artery

Purpose: Carotid artery stenting (CAS) has evolved as a first-line therapeutic option for carotid revascularization in indicated patients for stroke prevention, but there is still a lack of data on its effect on cognitive function (CF), especially among Indian patients. To determine the effect of CAS on CF and to study the immediate and delayed complications of CAS in Indian patients. Materials and Methods: This was a prospective, observational, single-center study. CF was assessed using Addenbrooke’s cognitive examination version III (ACE) before and 3 months after stenting. The demographic and clinical parameters were also assessed. A follow-up evaluation after 3 months was done to compare CF and to observe the occurrence of any complications. Results: Out of 31 patients, 3 were lost to follow up. There were no immediate or delayed procedure-related complications. There was a statistically significant improvement in overall ACE score and memory before and after stenting. On subgroup analysis of those with and without strokes, there was a significant improvement in visuospatial function and mean ACE score. Those with left CAS had significant improvement in memory, visuospatial, language, and ACE scores than right CAS. Conclusion CAS was associated with significant improvement in CF in patients.

Purpose: The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. Results: At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90–14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84–26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15–9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85–14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93–21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25–9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55–12.31; p = 0.005). Conclusions IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

Purpose: The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. Results: At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90–14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84–26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15–9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85–14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93–21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25–9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55–12.31; p = 0.005). Conclusions IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

BRAF is a serine/threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.