The interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N-ethyl-N-nitrosourea ...mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 (Oas2), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice.
To determine if sole activation of Oas2 could alter the course of mammary cancer, we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan-Meier survival analysis with immunohistochemistry and flow cytometry.
Oas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when the Oas2 mutation was present.
These data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.
Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte ...quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.
Display omitted
•Declining NAD(P)H is associated with oocyte dysfunction during reproductive aging•Oocyte quality and fertility can be restored by NMN treatment in aged mice•Supplementation of embryo media with NMN improves developmental milestones•SIRT2 overexpression mimics benefits of NMN but is unlikely to mediate its effects
Declining oocyte quality is considered an irreversible feature of aging and is rate limiting for human fertility. Bertoldo et al. show that reversing an age-dependent decline in NAD(P)H restores oocyte quality, embryo development, and functional fertility in aged mice. These findings may be relevant to reproductive medicine.
According to the U.S. Special Operations Command (SOCOM), new clinical trials of an anti-aging oral treatment using nicotinamide adenine nucleotide are planned for 2022. All over the globe, the ...discovery of the fountain of youth is still a great goal to reach, not only among aging researchers, since people desire to stay longer healthy and feel young when reaching old age. Since the 1960s, women delaying pregnancy to pursue higher educational levels and a career path has contributed to drastically diminished overall female fertility rates (e.g., number of born offspring/woman). Consequently, a growing number of advanced-aged women depend on assisted reproductive technologies (ART) to become pregnant. In 2019, the Society for Assisted Reproductive Technology reported 293,672 cycles for oocyte retrieval. This change of demographics influenced women’s age of having their first child, which has increased significantly. However, their reproductive tract shows hallmarks of aging very early in life without an effective preventive treatment. Therefore, we will present whether NAD+ could help to prevent oocyte aging.
Background and Aims: Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological ...approaches to prevent chemotherapy induced infertility are urgently needed. Here we investigate whether pharmacological elevation of nicotinamide adenine dinucleotide (NAD+) ameliorates chemotherapy induced female infertility in mice. Method: 8-week-old C57BL6 female mice were treated +/- chemotherapy (doxorubicin, Dox; 10 mg/kg) and +/- nicotinamide mononucleotide (NMN; 200 mg/kg i.p. once and 2 g/L in drinking water on-going), an orally bioavailable metabolic precursor to NAD+. Effects on fertility were measured by impact on ovarian reserve and folliculogenesis, ovulation rates and breeding performance. Effects on the ovarian NAD+ metabolome were assessed by mass spectrometry. A potential adverse effect of NMN on the efficiency of chemotherapy was assessed using a xenograft model of mammary cancer. Results: NMN treatment did not prevent a decline in the ovarian reserve caused by chemotherapy but did maintain the health of the remaining primordial follicle and total follicle populations, leading to a restoration in oocyte yield in chemo-treated mice (Dox vs Dox+NMN; P<0.007), culminating in an increase in pups born/mating in chemo+NMN treated mice (P<0.05). Chemo caused ovarian NMN, NADP+ and NADPH depletion, and NADPH was restored by NMN, which likely contributes to Dox detoxification. Importantly, treatment of the breast cancer mouse model with NMN reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Conclusion: Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function and fertility in cancer patients, with potential benefits in cancer therapy.
Background: Cancer survivors often face infertility as a result of ovarian toxicity from cytotoxic chemotherapy drugs, which trigger a cascade of events ultimately causing follicular reserve ...exhaustion and endocrine disruption. Apart from infertility, this can have severe consequences on women’s health with early-onset menopause and a decline in bone health. For girls with cancer, ovarian tissue cryopreservation (OTC) is the only option for fertility preservation. OTC + transplantation may provide future fertility potential, but it provides minimal/no protection from endocrine failure and osteoporosis.
Aim: To assess the effects of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) on ovarian function, fertility, and late-life bone health.
Method: 7-day old female mice were treated +/- cisplatin (2mg/kg). Two weeks later, +/- NMN was delivered in drinking water (2g/L) and sustained throughout life. A breeding trial was conducted at 6 weeks, and to assess late-life effects on bone structure, mice were maintained until euthanasia at 24 months of age.
Results: Cisplatin caused a dramatic decline in all fertility endpoints. NMN supplementation rescued breeding performance in cisplatin treated animals by 5-fold (p=0.015), as measured by the cumulative number of pups/female. Given the importance of ovarian function to estrogen release and the risk of osteoporosis, we sought to determine the impacts of these interventions on late-life bone health. Bones were subject to mechanical and structural analysis to assess differences in the onset of osteoporosis. In cisplatin treated animals, NMN rescued cortical bone thickness (femur diaphysis p
<
0.0001, femur metaphysis p=0.0081, tibia p=0.0072), bone volume (femur p=0.0015, tibia p=0.0102), and bone density (femur p=0.0463) to control levels, and increased mechanical strength (tibia, p=0.0024).
Conclusion: Long-term NMN treatment delivered following chemotherapy protected against subsequent ovarian failure and infertility, and notably improved late-life bone health, possibly due to the prevention of premature ovarian failure.
Airborne transmission of SARS-CoV-2 has been increasingly recognized in the outbreak of COVID-19, especially with the Omicron variant. We investigated an outbreak due to Omicron variant in a ...restaurant. Besides epidemiological and phylogenetic analyses, the secondary attack rates of customers of restaurant-related COVID-19 outbreak before (Outbreak R1) and after enhancement of indoor air dilution (Outbreak R2) were compared. On 27th December 2021, an index case stayed in restaurant R2 for 98 min. Except for 1 sitting in the same table, six other secondary cases sat in 3 corners at 3 different zones, which were served by different staff. The median exposure time was 34 min (range: 19–98 min). All 7 secondary cases were phylogenetically related to the index. Smoke test demonstrated that the airflow direction may explain the distribution of secondary cases. Compared with an earlier COVID-19 outbreak in another restaurant R1 (19th February 2021), which occurred prior to the mandatory enhancement of indoor air dilution, the secondary attack rate among customers in R2 was significantly lower than that in R1 (3.4%, 7/207 vs 28.9%, 22/76, p<0.001). Enhancement of indoor air dilution through ventilation and installation of air purifier could minimize the risk of SARS-CoV-2 transmission in the restaurants.
Display omitted
•SARS-CoV-2 is considered as a hazardous material.•Omicron variant is transmitted by airborne route.•Restaurant is a high-risk area for SARS-CoV-2 outbreak.•Enhanced indoor air dilution minimizes the number of infected cases.
Viral genomic surveillance is vital for understanding the transmission of COVID-19. In Hong Kong, breakthrough outbreaks have occurred in July (third wave) and November (fourth wave) 2020. We used ...whole viral genome analysis to study the characteristics of these waves.
We analyzed 509 SARS-CoV-2 genomes collected from Hong Kong patients between 22nd January and 29th November, 2020. Phylogenetic and phylodynamic analyses were performed, and were interpreted with epidemiological information.
During the third and fourth waves, diverse SARS-CoV-2 genomes were identified among imported infections. Conversely, local infections were dominated by a single lineage during each wave, with 96.6% (259/268) in the third wave and 100% (73/73) in the fourth wave belonging to B.1.1.63 and B.1.36.27 lineages, respectively. While B.1.1.63 lineage was imported 2 weeks before the beginning of the third wave, B.1.36.27 lineage has circulated in Hong Kong for 2 months prior to the fourth wave. During the fourth wave, 50.7% (37/73) of local infections in November was identical to the viral genome from an imported case in September. Within B.1.1.63 or B.1.36.27 lineage in our cohort, the most common non-synonymous mutations occurred at the helicase (nsp13) gene.
Although stringent measures have prevented most imported cases from spreading in Hong Kong, a single lineage with low-level local transmission in October and early November was responsible for the fourth wave. A superspreading event or lower temperature in November may have facilitated the spread of the B.1.36.27 lineage.
Richard and Carol Yu, Michael Tong, and the Government Consultancy Service (see acknowledgments for full list).
The coronavirus disease 2019 (COVID-19) has influenced antimicrobial consumption and incidence of multidrug-resistant organisms (MDROs). We aimed to study the epidemiology of MDROs before and during ...the COVID-19 pandemic in Hong Kong.
With the maintenance of infection control measures, we described the trend of MDRO infections, including methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Acinetobacter species (CRA), and extended-spectrum-beta-lactamase-(ESBL)-producing Enterobacterales, in a healthcare region with 3100-bed before (1 January 2016 to 31 December 2019, period 1) and during COVID-19 (1 January 2020 to 30 September 2022, period 2), together with the antimicrobial consumption using piecewise Poisson regression. The epidemiological characteristics of newly diagnosed COVID-19 patients with or without MDRO infections were analyzed.
Between period 1 and 2, we observed a significant increase in the trend of CRA infections (P<0.001), while there was no significant increase in the trend of MRSA (P=0.742) and ESBL-producing Enterobacterales (P=0.061) infections. Meanwhile, a significant increase in the trend of carbapenems (P<0.001), extended-spectrum beta-lactam-beta-lactamase inhibitor combinations (BLBI) (P=0.045), and fluoroquinolones (P=0.009) consumption was observed. The observed opportunity (23,540 ± 3703 vs 26,145 ± 2838, p=0.359) and compliance (81.6% ± 0.5% vs 80.1% ± 0.8%, P=0.209) of hand hygiene per year was maintained. In a multivariable model, older age, male sex, referral from residential care home for the elderly, presence of indwelling device, presence of endotracheal tube, and use of carbapenems, use of BLBI, use of proton pump inhibitors and history of hospitalization in the past 3 months were associated with higher risks of infections by MDROs among COVID-19 patients.
Infection control measures may control the surge of MDROs despite an increasing trend of antimicrobial consumption.
SARS-CoV-2 has evolved rapidly into several genetic clusters. However, data on mutations during the course of infection are scarce. This study aims to determine viral genome diversity in serial ...samples of COVID-19 patients.
Targeted deep sequencing of the spike gene was performed on serial respiratory specimens from COVID-19 patients using nanopore and Illumina sequencing. Sanger sequencing was then performed to confirm the single nucleotide polymorphisms.
A total of 28 serial respiratory specimens from 12 patients were successfully sequenced using nanopore and Illumina sequencing. A 75-year-old patient with severe disease had a mutation, G22017T, identified in the second specimen. The frequency of G22017T increased from ≤5% (nanopore: 3.8%; Illumina: 5%) from the first respiratory tract specimen (sputum) to ≥60% (nanopore: 67.7%; Illumina: 60.4%) in the second specimen (saliva; collected 2 days after the first specimen). The difference in G22017T frequency was also confirmed by Sanger sequencing. G22017T corresponds to W152L amino acid mutation in the spike protein which was only found in <0.03% of the sequences deposited into a public database. Spike amino acid residue 152 is located within the N-terminal domain, which mediates the binding of a neutralizing antibody.
A spike protein amino acid mutation W152L located within a neutralizing epitope has appeared naturally in a patient. Our study demonstrated that monitoring of serial specimens is important in identifying hotspots of mutations, especially those occurring at neutralizing epitopes which may affect the therapeutic efficacy of monoclonal antibodies.
PDF
