Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Understanding Obesity: The Role of Adipose Tissue Microenvironment and the Gut Microbiome.

The prevalence of obesity has more than doubled globally over the past few decades, with a 12-fold rise in extreme levels. Obesity, with its multiple complications, remains a major ongoing challenge for health-care professionals, as highlighted by the COVID-19 pandemic, where people with obesity had poorer outcomes. In this article, we review advances in our understanding of the pathophysiology underlying obesity, with a focus on the immune system and its interaction with both the adipose tissue organ and the gut microbiome. As our understanding of the causes and effects of obesity improves, opportunities should emerge, underpinned by rigorous laboratory and clinical research, to both better prevent and treat this global epidemic.

Complete Genome Sequence of Cluster J Mycobacteriophage Superphikiman.

Mycobacteriophage Superphikiman is a cluster J bacteriophage which was isolated from soil collected in Philadelphia, PA. Superphikiman has a 109,799-bp genome with 239 predicted genes, including 2 tRNA genes.

Variation of indoor radon concentrations in two-storey houses in Nowshera District, Pakistan.

A study was performed for the measurement of indoor radon concentration in two-storey houses in district Nowshera in the Khyber Pakhtunkhwa province of Pakistan. This area was not previously surveyed for such kind of study. The aim was to find some correlation of radon levels in first and second storey houses in the area. The measurements were carried out for 1 y from 1 December 2012 to 30 November 2013 using CR-39 detector. The area was divided into four parts, namely, Jhangera, Nowshera city, Akora Khattak and Pabbi. In the first storey houses, radon concentration ranged from 29 to 103 Bq m(-3) with the mean value of 64 ± 12 Bq m(-3) and that in the second storey houses ranged from 25 to 92 Bq m(-3) with the mean value of 56 ± 11 Bq m(-3). Relatively higher values of indoor radon levels in the first stories than the second stories were observed in all four parts of the study area. The effective doses received by the residents of the area were estimated for each part. The mean annual effective doses received by the inhabitants of the area from indoor radon ranged from 0.68 to 2.88 mSv with the mean value of 1.68 ± 0.32 mSv. The doses received by the people of the area were within the ICRP-65 recommended range (3-10 mSv).

Prevalence of ocular pseudoexfoliation syndrome and associated complications in Riyadh, Saudi Arabia.

OBJECTIVES: To assess the prevalence of pseudoexfoliation syndrome (PEX), and associated ophthalmic complications among Saudi patients. METHODS: The prevalence of PEX and associated ocular co-morbidities were determined among the Saudi patients visiting the Primary Care Clinic of Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia, between January 2009 and January 2010. A total of 1967 patients were examined biomicoscopically by ophthalmologists to determine the presence of PEX and associated ocular complications. RESULTS: Sixty-nine of the 1967 examined patients (3.5%) showed the presence of PEX with no significant gender difference. There was an age dependent increase in the prevalence of PEX after the age of 50 years. Pseudoexfoliation syndrome was associated with higher intraocular pressure, cataract, and poor vision. There was no significant difference in the prevalence of PEX in male and female Saudi patients. CONCLUSION: Pseudoexfoliation syndrome is an age-related disorder, and its prevalence increases with age. Further larger population based studies are warranted to assess the prevalence of PEX and associated risk factors.