Pan-cancer mutational signature surveys correlated mutational signature with geospatial environmental exposures and viral infections.

Background: Cancer has been disproportionally affecting minorities. Genomic-based cancer disparity analyses have been less common than conventional epidemiological studies. In the past decade, mutational signatures have been established as characteristic footprints of endogenous or exogenous carcinogens. Methods: Integrating datasets of diverse cancer types from The Cancer Genome Atlas and geospatial environmental risks of the registry hospitals from the United States Environmental Protection Agency, we explored mutational signatures from the aspect of racial disparity concerning pollutant exposures. The raw geospatial environmental exposure data were refined to 449 air pollutants archived and modeled from 2007 to 2017 and aggregated to the census county level. Additionally, hepatitis B and C viruses and human papillomavirus infection statuses were incorporated into analyses for skin cancer, cervical cancer, and liver cancer. Results: Mutation frequencies of key oncogenic genes varied substantially between different races. These differences were further translated into differences in mutational signatures. Survival analysis revealed that the increased pollution level is associated with worse survival. The analysis of the oncogenic virus revealed that aflatoxin, an affirmed carcinogen for liver cancer, was higher in Asian liver cancer patients than in White patients. The aflatoxin mutational signature was exacerbated by hepatitis infection for Asian patients but not for White patients, suggesting a predisposed genetic or genomic disadvantage for Asians concerning aflatoxin. Conclusions: Environmental pollutant exposures increase a mutational signature level and worsen cancer prognosis, presenting a definite adverse risk factor for cancer patients.

TET3 plays a critical role in white adipose development and diet-induced remodeling.

Maintaining healthy adipose tissue is crucial for metabolic health, requiring a deeper understanding of adipocyte development and response to high-calorie diets. This study highlights the importance of TET3 during white adipose tissue (WAT) development and expansion. Selective depletion of Tet3 in adipose precursor cells (APCs) reduces adipogenesis, protects against diet-induced adipose expansion, and enhances whole-body metabolism. Transcriptomic analysis of wild-type and Tet3 knockout (KO) APCs unveiled TET3 target genes, including Pparg and several genes linked to the extracellular matrix, pivotal for adipogenesis and remodeling. DNA methylation profiling and functional studies underscore the importance of DNA demethylation in gene regulation. Remarkably, targeted DNA demethylation at the Pparg promoter restored its transcription. In conclusion, TET3 significantly governs adipogenesis and diet-induced adipose expansion by regulating key target genes in APCs.

AIFM2 Is Required for High-Intensity Aerobic Exercise in Promoting Glucose Utilization.

Skeletal muscle is a major regulator of glycemic control at rest, and glucose utilization increases drastically during exercise. Sustaining a high glucose utilization via glycolysis requires efficient replenishment of NAD+ in the cytosol. Apoptosis-inducing mitochondrion-associated factor 2 (AIFM2) was previously shown to be a NADH oxidoreductase domain-containing flavoprotein that promotes glycolysis for diet and cold-induced thermogenesis. Here, we find that AIFM2 is selectively and highly induced in glycolytic extensor digitorum longus (EDL) muscle during exercise. Overexpression (OE) of AIFM2 in myotubes is sufficient to elevate the NAD+-to-NADH ratio, increasing the glycolytic rate. Thus, OE of AIFM2 in skeletal muscle greatly increases exercise capacity, with increased glucose utilization. Conversely, muscle-specific Aifm2 depletion via in vivo transfection of hairpins against Aifm2 or tamoxifen-inducible haploinsufficiency of Aifm2 in muscles decreases exercise capacity and glucose utilization in mice. Moreover, muscle-specific introduction of NDE1, Saccharomyces cerevisiae external NADH dehydrogenase (NDE), ameliorates impairment in glucose utilization and exercise intolerance of the muscle-specific Aifm2 haploinsufficient mice. Together, we show a novel role for AIFM2 as a critical metabolic regulator for efficient utilization of glucose in glycolytic EDL muscles.

Age-dependent alterations in the number, volume, and localization of islands of Calleja within the olfactory tubercle.

The incidence of olfactory perceptual dysfunction increases substantially with aging. Putative mechanisms for olfactory sensory loss are surfacing, including neuroanatomical modifications within brain regions responsible for odor information processing. The islands of Calleja (IC) are dense cell clusters localized within the olfactory tubercle, a cortical structure receiving monosynaptic input from the olfactory bulb. The IC are hypothesized to be important for intra- and extra-olfactory tubercle information processing, and thus olfaction. However, whether the anatomy of the IC are affected throughout normal aging remains unclear. By examining the IC of C57bl/6 mice throughout adulthood and early aging (4-18 months of age), we found that the number of IC decreases significantly with aging. Stereological analysis revealed that the remaining IC in 18-month-old mice were significantly reduced in estimated volume compared with those in 4- month-old mice. We additionally found that whereas young adults (4 months of age) possess greater numbers of IC within the posterior parts of the olfactory tubercle, by 18 months of age, a greater percentage of IC are found within the anterior-most part of the olfactory tubercle, perhaps providing a substrate for the differential access of the IC to odor information throughout aging. These results show that the IC are highly plastic components of the olfactory cortex, changing in volume, localization, and even number throughout normal aging. We predict that modifications among the IC throughout aging and age-related neurodegenerative disorders might be a novel contributor to pathological changes in olfactory cortex function and olfactory perception.

Peptide transporter 1 is responsible for intestinal uptake of the dipeptide glycylsarcosine: studies in everted jejunal rings from wild-type and Pept1 null mice.

The purpose of this study was to determine the relative importance of peptide transporter 1 (PEPT1) in the uptake of peptides/mimetics from mouse small intestine, using glycylsarcosine (GlySar). After isolating jejunal tissue from wild-type and Pept1 null mice, 2 cm intestinal segments were everted and mounted on glass rods for tissue uptake studies. [(14)C]GlySar (4 µM) was studied as a function of time, temperature, sodium and pH, concentration, and potential inhibitors. Compared with wild-type animals, Pept1 null mice exhibited a 78% reduction in GlySar uptake at pH 6.0 at 37°C. GlySar uptake showed pH dependence, with peak values between pH 6.0 and 6.5 in wild-type animals, whereas no such tendency was observed in Pept1 null mice. GlySar exhibited Michaelis-Menten uptake kinetics and a minor nonsaturable component in wild-type animals. In contrast, GlySar uptake occurred only by a nonsaturable process in Pept1 null mice. GlySar uptake was significantly inhibited by dipeptides, aminocephalosporins, angiotensin-converting enzyme inhibitors, and the antiviral prodrug valacyclovir; these inhibitors had little, if any, effect on the uptake of GlySar in Pept1 null mice. The findings demonstrate that PEPT1 plays a critical role in the uptake of GlySar in jejunum and suggest that PEPT1 is the major transporter responsible for the intestinal absorption of small peptides.

Beyond the X's and Y's: A case of complete androgen insensitivity syndrome

The Sex or sexuality is very complex subject. From a biological standpoint, the appearance of the external genitalia is only one parameter. Complete androgen insensitivity syndrome (CAIS), the most common form of male pseudohermaphroditism, embodies the multifaceted nature of this concept. Patients usually present with 46, XY karyotype with bilateral testes, female external genitalia, a shortened vagina, absent or rudimentary mullerian derivatives, normal breast development, and absent or scant pubic and axillary hair, as was the case in the patient presented herein. Prevalence ranges from 1 :20,400 to 1 :62,400 births. Its management often requires a multidisciplinary approach. Aside from addressing health risks, the psychosexual, social and ethical aspects of this condition should also be dealt with.

The incidence of osteoporosis among Filipino based on calcaneal quantitative ultrasonography

With the aging of the world's population, osteoporosis has emerged as a formidable health concern. Bone mineral density (BMD) is the only available clinical parameter for bone strength evaluation and is determined through the use of dual energy x-ray absorptiometry (DEXA), the gold standard for the diagnosis of osteoporosis, and peripheral DEXA, such as calcaneal quantitative ultrasonography (QUS). This is a cross-sectional, descriptive study which aimed to determine the prevalence of osteoporosis among Filipinos, based on T-scores utilizing calcaneal quantitative ultrasonography. Baseline bone mineral density of 20,726 Filipinos were gathered based on the T-scores from calcaneal quantitative ultrasound results. The WHO criteria standardized the classification of BMD based on T-scores. Results showed that 3 percent of Filipinos were osteoporotic, 22 percent were osteopenic, while the rest were normal. The female sex and advanced age were key determinants of osteoporotic risk wheareas geographic location appears to have no influence.

The effect of gum-chewing in the resolution of postoperative ileus following gynecologic laparoscopic surgery: a randomized controlled trial

Early feeding is advocated for the resolution of postoperative ileus. After gynecologic laparoscopy, patients usually resume regular diet once the anesthesia has resolved. Gum-chewing is a form of sham feeding which may stimulate gut motility via vagal cholinergic stimulation. This study aimed to determine if gum-chewing is comparable to early feeding in the resolution of postopreative ileus. Thirty patients undergoing elective gynecologic laparoscopic surgery surgery were randomized to the control group, who immediately resumed regular diet, and the gum-chewing group, who were asked to chew gum three times a day until passage of flatus. The mean was operative times were comparable. The time to passage of first flatus of the control group was 22.675 hours while that of the gum-chewing group was 23.174. The difference between the was not significant with a P value of 0.8185. Gum-chewing is comparable to early feeding in the resolution of postoperative ileus.

Prospective clinical evaluation of patients from Missouri and New York with erythema migrans-like skin lesions.

BACKGROUND: The most common and most recognizable feature of Borrelia burgdorferi infection (Lyme disease) is the skin lesion erythema migrans (EM). An illness associated with an EM-like skin lesion, but which is not caused by B. burgdorferi, occurs in many southern states in the United States (southern tick-associated rash illness [STARI], also known as Masters disease). METHODS: Clinical features of 21 cases of EM-like skin lesions in 21 patients from Missouri were compared in a prospective study with those of 101 cases in 97 patients with EM-like skin lesions from New York. RESULTS: Among Missouri cases, the peak incidence of EM-like skin lesions occurred earlier in the year than it did among New York cases (P<.001). Case patients from Missouri were more likely to recall a tick bite than were case patients from New York (85.7% and 19.8%, respectively; P<.001), and the time period from tick bite to onset of the skin lesion was shorter among Missouri case patients (6.1+/-4.2 days and 10.4+/-6.1 days, respectively; P=.011). Missouri case patients were less likely to be symptomatic than were New York case patients (19.0% and 76.2%, respectively; P<.001), and Missouri case patients were less likely to have multiple skin lesions (4.8% and 26.7%, respectively; P=.042). EM-like lesions in Missouri cases were smaller in size than those in New York cases (8.3+/-2.2 cm and 16.4+/-11.5 cm, respectively; P<.001), more circular in shape (P=.004), and more likely to have central clearing (76.2% and 21.6%, respectively; P<.001). After antibiotic treatment, Missouri case patients recovered more rapidly than did New York case patients (P=.037). CONCLUSION: Cases of EM-like skin lesion in patients from Missouri and New York have distinct clinical presentations.