Therapeutic validation of MMR-associated genetic modifiers in a human ex vivo model of Huntington disease.

The pathological huntingtin (HTT) trinucleotide repeat underlying Huntington disease (HD) continues to expand throughout life. Repeat length correlates both with earlier age at onset (AaO) and faster progression, making slowing its expansion an attractive therapeutic approach. Genome-wide association studies have identified candidate variants associated with altered AaO and progression, with many found in DNA mismatch repair (MMR)-associated genes. We examine whether lowering expression of these genes affects the rate of repeat expansion in human ex vivo models using HD iPSCs and HD iPSC-derived striatal medium spiny neuron-enriched cultures. We have generated a stable CRISPR interference HD iPSC line in which we can specifically and efficiently lower gene expression from a donor carrying over 125 CAG repeats. Lowering expression of each member of the MMR complexes MutS (MSH2, MSH3, and MSH6), MutL (MLH1, PMS1, PMS2, and MLH3), and LIG1 resulted in characteristic MMR deficiencies. Reduced MSH2, MSH3, and MLH1 slowed repeat expansion to the largest degree, while lowering either PMS1, PMS2, or MLH3 slowed it to a lesser degree. These effects were recapitulated in iPSC-derived striatal cultures where MutL factor expression was lowered. CRISPRi-mediated lowering of key MMR factor expression to levels feasibly achievable by current therapeutic approaches was able to effectively slow the expansion of the HTT CAG tract. We highlight members of the MutL family as potential targets to slow pathogenic repeat expansion with the aim to delay onset and progression of HD and potentially other repeat expansion disorders exhibiting somatic instability.

The optimized Fenton-like activity of Fe single-atom sites by Fe atomic clusters-mediated electronic configuration modulation.

The performance optimization of isolated atomically dispersed metal active sites is critical but challenging. Here, TiO2@Fe species-N-C catalysts with Fe atomic clusters (ACs) and satellite Fe-N4 active sites were fabricated to initiate peroxymonosulfate (PMS) oxidation reaction. The AC-induced charge redistribution of single atoms (SAs) was verified, thus strengthening the interaction between SAs and PMS. In detail, the incorporation of ACs optimized the HSO5- oxidation and SO5·- desorption steps, accelerating the reaction progress. As a result, the Vis/TiFeAS/PMS system rapidly eliminated 90.81% of 45 mg/L tetracycline (TC) in 10 min. The reaction process characterization suggested that PMS as an electron donor would transfer electron to Fe species in TiFeAS, generating 1O2. Subsequently, the hVB+ can induce the generation of electron-deficient Fe species, promoting the reaction circulation. This work provides a strategy to construct catalysts with multiple atom assembly-enabled composite active sites for high-efficiency PMS-based advanced oxidation processes (AOPs).

Generating dual-active species by triple-atom sites through peroxymonosulfate activation for treating micropollutants in complex water.

The peroxymonosulfate (PMS)-triggered radical and nonradical active species can synergistically guarantee selectively removing micropollutants in complex wastewater; however, realizing this on heterogeneous metal-based catalysts with single active sites remains challenging due to insufficient electron cycle. Herein, we design asymmetric Co-O-Bi triple-atom sites in Co-doped Bi2O2CO3 to facilitate PMS oxidation and reduction simultaneously by enhancing the electron transfer between the active sites. We propose that the asymmetric Co-O-Bi sites result in an electron density increase in the Bi sites and decrease in the Co sites, thereby PMS undergoes a reduction reaction to generate SO4•- and •OH at the Bi site and an oxidation reaction to generate 1O2 at the Co site. We suggest that the synergistic effect of SO4•-, •OH, and 1O2 enables efficient removal and mineralization of micropollutants without interference from organic and inorganic compounds under the environmental background. As a result, the Co-doped Bi2O2CO3 achieves almost 99.3% sulfamethoxazole degradation in 3 min with a k-value as high as 82.95 min-1 M-1, which is superior to the existing catalysts reported so far. This work provides a structural regulation of the active sites approach to control the catalytic function, which will guide the rational design of Fenton-like catalysts.

MutLα suppresses error-prone DNA mismatch repair and preferentially protects noncoding DNA from mutations.

The DNA mismatch repair (MMR) system promotes genome stability and protects humans from certain types of cancer. Its primary function is the correction of DNA polymerase errors. MutLα is an important eukaryotic MMR factor. We have examined the contributions of MutLα to maintaining genome stability. We show here that loss of MutLα in yeast increases the genome-wide mutation rate by ∼130-fold and generates a genome-wide mutation spectrum that consists of small indels and base substitutions. We also show that loss of yeast MutLα leads to error-prone MMR that produces T > C base substitutions in 5'-ATA-3' sequences. In agreement with this finding, our examination of human whole-genome DNA sequencing data has revealed that loss of MutLα in induced pluripotent stem cells triggers error-prone MMR that leads to the formation of T > C mutations in 5'-NTN-3' sequences. Our further analysis has shown that MutLα-independent MMR plays a role in suppressing base substitutions in N3 homopolymeric runs. In addition, we describe that MutLα preferentially protects noncoding DNA from mutations. Our study defines the contributions of MutLα-dependent and independent mechanisms to genome-wide MMR.

Electron delocalization triggers nonradical Fenton-like catalysis over spinel oxides.

Nonradical Fenton-like catalysis offers opportunities to overcome the low efficiency and secondary pollution limitations of existing advanced oxidation decontamination technologies, but realizing this on transition metal spinel oxide catalysts remains challenging due to insufficient understanding of their catalytic mechanisms. Here, we explore the origins of catalytic selectivity of Fe-Mn spinel oxide and identify electron delocalization of the surface metal active site as the key driver of its nonradical catalysis. Through fine-tuning the crystal geometry to trigger Fe-Mn superexchange interaction at the spinel octahedra, ZnFeMnO4 with high-degree electron delocalization of the Mn-O unit was created to enable near 100% nonradical activation of peroxymonosulfate (PMS) at unprecedented utilization efficiency. The resulting surface-bound PMS* complex can efficiently oxidize electron-rich pollutants with extraordinary degradation activity, selectivity, and good environmental robustness to favor water decontamination applications. Our work provides a molecule-level understanding of the catalytic selectivity and bimetallic interactions of Fe-Mn spinel oxides, which may guide the design of low-cost spinel oxides for more selective and efficient decontamination applications.

PMS2 or PMS2CL? Characterization of variants detected in the 3' of the PMS2 gene.

PMS2 germline pathogenic variants are one of the major causes for Lynch syndrome and constitutional mismatch repair deficiencies. Variant identification in the 3' region of this gene is complicated by the presence of the pseudogene PMS2CL which shares a high sequence homology with PMS2. Consequently, short-fragment screening strategies (NGS, Sanger) may fail to discriminate variant's gene localization. Using a comprehensive analysis strategy, we assessed 42 NGS-detected variants in 76 patients and found 32 localized on PMS2 while 6 on PMS2CL. Interestingly, four variants were detected in either of them in different patients. Clinical phenotype was well correlated to genotype, making it very helpful in variant assessment. Our findings emphasize the necessity of more specific complementary analyses to confirm the gene origin of each variant detected in different individuals in order to avoid variant misinterpretation. In addition, we characterized two PMS2 genomic alterations involving Alu-mediated tandem duplication and gene conversion. Those mechanisms seemed to be particularly favored in PMS2 which contribute to frequent genomic rearrangements in the 3' region of the gene.

PMS2 amplification contributes brain metastasis from lung cancer.

BACKGROUND: Lung adenocarcinoma metastasizing to the brain results in a notable increase in patient mortality. The high incidence and its impact on survival presents a critical unmet need to develop an improved understanding of its mechanisms. METHODS: To identify genes that drive brain metastasis of tumor cells, we collected cerebrospinal fluid samples and paired plasma samples from 114 lung adenocarcinoma patients with brain metastasis and performed 168 panel-targeted gene sequencing. We examined the biological behavior of PMS2 (PMS1 Homolog 2)-amplified lung cancer cell lines through wound healing assays and migration assays. In vivo imaging techniques are used to detect fluorescent signals that colonize the mouse brain. RNA sequencing was used to compare differentially expressed genes between PMS2 amplification and wild-type lung cancer cell lines. RESULTS: We discovered that PMS2 amplification was a plausible candidate driver of brain metastasis. Via in vivo and in vitro assays, we validated that PMS2 amplified PC-9 and LLC lung cancer cells had strong migration and invasion capabilities. The functional pathway of PMS2 amplification of lung cancer cells is mainly enriched in thiamine, butanoate, glutathione metabolism. CONCLUSION: Tumor cells elevated expression of PMS2 possess the capacity to augment the metastatic potential of lung cancer and establish colonies within the brain through metabolism pathways.

Synergistic Coordination in Cu Single-Atom Catalysts Enhances High-Valent Copper-Oxo Species for Efficient PMS Activation.

In the domain of heterogeneous catalytic activation of peroxymonosulfate (PMS), high-valent metal-oxo (HVMO) species are widely recognized as potent oxidants for the abatement of organic pollutants. However, the generation selectivity and efficiency of HVMO are often constrained by stringent requirements for catalyst adsorption sites and electron transfer efficiency. In this study, a single-atom catalyst, CuSA/CNP&S, is synthesized featuring multiple types (planar/axial) of heteroatom coordination via an H-bond-assisted self-assembly strategy. It is confirmed that CuN3 active centers with axial S coordination are uniformly distributed in a carbon matrix modified by planar P atoms. CuSA/CNP&S activated PMS to selectively generate Cu(III)═OH species as the primary reactive oxygen species (ROS). The pseudo-first-order kinetic rate for bisphenol A degradation reached 1.51 min-1, a 17.57-fold increase compared to the unmodified CuSA/CN catalyst. Additionally, the CuSA/CNP&S catalyst demonstrates high efficiency and durability in removing contaminants from various aqueous matrices. Theoretical calculations and experimental results indicate that the intrinsic electric field generated by distal planar P atoms enhances electron transfer efficiency within the carbon matrix. Meanwhile, axial S coordination elevates the d-band center and tunes the eg * band broadening of Cu, thereby enhancing the adsorption selectivity for the terminal oxygen of PMS. This multitype coordination synergistically mitigates the issues of low selectivity and yield of HVMO species.

Blocking reverse electron transfer-mediated mitochondrial DNA oxidation rescues cells from PANoptosis.

PANoptosis is a new type of cell death featured with pyroptosis, apoptosis and necroptosis, and is implicated in organ injury and mortality in various inflammatory diseases, such as sepsis and hemophagocytic lymphohistiocytosis (HLH). Reverse electron transport (RET)-mediated mitochondrial reactive oxygen species (mtROS) has been shown to contribute to pyroptosis and necroptosis. In this study we investigated the roles of mtROS and RET in PANoptosis induced by TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (Oxo) plus lipopolysaccharide (LPS) as well as the effects of anti-RET reagents on PANoptosis. We showed that pretreatment with anti-RET reagents 1-methoxy PMS (MPMS) or dimethyl fumarate (DMF) dose-dependently inhibited PANoptosis in macrophages BMDMs and J774A.1 cells induced by Oxo/LPS treatment assayed by propidium iodide (PI) staining. The three arms of the PANoptosis signaling pathway, namely pyroptosis, apoptosis and necroptosis signaling, as well as the formation of PANoptosomes were all inhibited by MPMS or DMF. We demonstrated that Oxo/LPS treatment induced RET and mtROS in BMDMs, which were reversed by MPMS or DMF pretreatment. Interestingly, the PANoptosome was co-located with mitochondria, in which the mitochondrial DNA was oxidized. MPMS and DMF fully blocked the mtROS production and the formation of PANoptosome induced by Oxo plus LPS treatment. An HLH mouse model was established by poly(I:C)/LPS challenge. Pretreatment with DMF (50 mg·kg-1·d-1, i.g. for 3 days) or MPMS (10 mg·kg-1·d-1, i.p. for 2 days) (DMF i.g. MPMS i.p.) effectively alleviated HLH lesions accompanied by decreased hallmarks of PANoptosis in the liver and kidney. Collectively, RET and mtDNA play crucial roles in PANoptosis induction and anti-RET reagents represent a novel class of PANoptosis inhibitors by blocking oxidation of mtDNA, highlighting their potential application in treating PANoptosis-related inflammatory diseases. PANoptotic stimulation induces reverse electron transport (RET) and reactive oxygen species (ROS) in mitochondia, while 1-methoxy PMS and dimethyl fumarate can inhibit PANoptosis by suppressing RETmediated oxidation of mitochondrial DNA.

Effective degradation of phenol by activating PMS with bimetallic Mo and Ni Co-doped g C3N4 composite catalyst: A Fenton-like degradation process promoted by non-free radical 1O2.

The application of bimetal supported graphite phase carbon nitride in activated peroxymonosulfate (PMS) process has become a research hotspot in recent years. In this study, 8-g C3N4/Mo/Ni composite catalyst material was successfully prepared by doping Mo and Ni in graphite phase carbon nitride. The bimetallic active sites were formed in the catalyst, and PMS was activated by the metal valence Mo6+/Mo4+ and Ni2+/Ni(0) through redox double cycle to effectively degrade phenol. When pH was neutral, the degradation rate of 20 mg/L phenol solution with 8-g C3N4/Mo/Ni (0.35 g/L) and PMS (0.6 mM) could reach 95% within 20 min. The degradation rate of 8-g C3N4/Mo/Ni/PMS catalytic system could reach more than 90% within 20min under the condition of pH range of 3-11 and different anions. Meanwhile, the degradation effects of RhB, MB and OFX on different pollutants within 30min were 99%, 100% and 82%, respectively. Electron spin resonance and quenching experiments showed that in 8-g C3N4/Mo/Ni/PMS system, the degradation mechanism was mainly non-free radicals, and the main active species in the degradation process was 1O2. This study provides a new idea for the study of bimetal supported graphite phase carbon nitride activation of PMS and the theoretical study of degradation mechanism.

Discerning the role of a site cation in ACoO3 perovskites for boosting Co3+/Co2+ redox cycle for pollutant degradation: DFT calculation, mechanism and toxicity evolution.

The degradation of persistent and refractory pollutants, particularly plastic and resins manufacturing wastewater, poses a significant challenge due to their high toxicity and high concentrations. This study developed a novel hybrid ACoO3 (A = La, Ce, Sr)/PMS perovskite system for the treatment of multicomponent (MCs; ACN, ACM and ACY) from synthetic resin manufacturing wastewater. Synthesized perovskites were characterized by various techniques i.e., BET, XRD, FESEM with EDAX, FTIR, TEM, XPS, EIS, and Tafel analysis. Perovskite LaCoO3 exhibited the highest degradation of MCs i.e., ACN (98.7%), ACM (86.3%), and ACY (56.4%), with consumption of PMS (95.2%) under the optimal operating conditions (LaCoO3 dose 0.8 g/L, PMS dose 2 g/L, pH 7.2 and reaction temperature 55 °C). The quantitative contribution (%) of reactive oxygen species (ROS) reveals that SO4•- are the dominating radical species, which contribute to ACN (58.3% for SO4•- radicals) and ACM degradation (46.4% for SO4•- radicals). The tafel plots and EIS spectra demonstrated that perovskites LaCoO3 have better charge transfer rates and more reactive sites that are favorable for PMS activation. Further, four major degradation pathways were proposed based on Fukui index calculations, as well as GC-MS characterization of intermediate byproducts. Based on a stability and reusability study, it was concluded that LaCoO3 perovskites are highly stable, and minimal cobalt leaching occurs (0.96 mg/L) after four cycles. The eco-toxicity assessment performed using QSAR model indicated that the byproducts of the LaCoO3/PMS system are non-toxic nature to common organism (i.e., fish, daphnids and green algae). In addition, the cost of the hybrid LaCoO3/PMS system in a single cycle was estimated to be $34.79 per cubic meter of resin wastewater.

Peroxymonosulfate activation by walnut shell activated carbon supported nano zero-valent iron for the degradation of tetracycline: Performance, degradation pathway and mechanism.

In this study, activated carbon (WS-AC) was prepared from walnut shell. Nano-zero-valent iron (nZVI) was loaded on walnut shell activated carbon by liquid phase reduction method and used as catalyst (WS-AC/nZVI) to activate peroxymonosulfate (PMS) to efficiently degrade tetracycline (TC) in solution. The composite material with a mass ratio of WS-AC to nZVI of 1:1 has the highest catalytic performance for activating PMS to degrade TC. The results showed that under the conditions of TC concentration of 100 ppm, PMS dosage of 0.2 mM and WS-AC/nZVI dosage of 0.1 g/L, the removal efficiency of TC could reach 81%. Based on quenching experiments and electron spin resonance (EPR), it was verified that •OH, SO4•- and 1O2 bound on the catalyst surface were the main reactive oxygen species during the reaction. The intermediate products of TC were identified by liquid chromatography-mass spectrometry (HPLC-MS) and DFT calculation, and the possible degradation pathway of TC was proposed. The catalyst still maintained high removal efficiency of TC after four cycles of experiments, and the minimal iron loss on the surface of the catalyst indicated that it had good stability. The efficient and stable WS-AC/nZVI activated PMS showed great potential in the degradation of antibiotics.

Theory-guided unraveling of the mechanism underlying Cu1.0/Mn1.0-ZnO with dual reaction centers for enhanced peroxymonosulfate activation.

Developing efficient catalytic systems for water contamination removal is a topic of great interest. However, the use of heterogeneous catalysts faces challenges due to insufficient active sites and electron cycling. In this study, results from first-principles calculations demonstrate that dual reaction centers (DRCs) are produced around the Cu and Mn sites in Cu1.0/Mn1.0-ZnO due to the electronegativity difference. Experimental results reveal the material with DRCs greatly enhances electron transfer efficiency and significantly impacts the oxidation and reduction of peroxymonosulfate (PMS). In addition, the self-consistent potential correction (SCPC) method was introduced to correct the energy and charge of charged periodic systems simulating a catalytic process, resulting in more precise catalytic results. Specifically, the material exhibits a preference for adsorbing negatively charged PMS anions at electron-deficient Mn sites, facilitating PMS oxidation for the generation of 1O2, and PMS reduction around the electron-rich Cu for the formation of •OH and SO4•-. The major reactive oxygen species is 1O2, showcasing effective performance in various degradation systems. Overall, our work provides novel insights into the persulfate-based heterogeneous catalytic oxidation process, paving the way for the development of high-performance catalytic systems for water purification.

Integrating g-C3N4 nanosheets with MOF-derived porous CoFe2O4 to form an S-scheme heterojunction for efficient pollutant degradation via the synergy of photocatalysis and peroxymonosulfate activation.

When confronted with wastewater that is characterized by complex composition, stable molecular structure, and high concentration, relying solely on photocatalytic technology proves inadequate in achieving satisfactory degradation results. Therefore, the integration of other highly efficient degradation techniques has emerged as a viable approach to address this challenge. Herein, a novel strategy was employed whereby the exfoliated g-C3N4 nanosheets (CNs) with exceptional photocatalytic performance, were intimately combined with porous rod-shaped cobalt ferrite (CFO) through a co-calcination process to form the composite CFO/CNs, which exhibited remarkable efficacy in the degradation of various organic pollutants through the combination of photocatalysis and Fenton-like process synergistically, exemplified by the representative case of tetracycline hydrochloride (TCH, 200 mL, 50 mg/L). Specifically, under 1 mM of peroxymonosulfate (PMS) and illumination conditions, 50 mg of 1CFO/9CNs achieved a TCH removal ratio of ∼90% after 60 min of treatment. Furthermore, this work comprehensively investigated the influence of various factors, including catalyst and PMS dosages, solution pH, and the presence of anions and humate, on the degradation efficiency of pollutants. Besides, quenching experiments and EPR tests confirmed the establishment of an S-scheme heterojunction between CNs and CFO, which facilitated the effective spatial separation of photoexcited charge carriers and preserved the potent redox potential of photogenerated electrons and holes. This work offers a valuable reference for the integration of photocatalysis with the PMS-based Fenton-like process.

Degradation of trichloroacetic acid by Fe/Ni bimetallic reactive PMS with hierarchical layered structure.

Overuse of chlorinated disinfectants leads to a significant accumulation of disinfection by-products. Trichloroacetic acid (TCA) is a typical carcinogenic disinfection by-product. The efficacy of the conventional degradation process is reduced by the complex nature of its structure, causing a yearly increase in its prevalence within the ecological environment and consequent infliction of significant harm. In this paper, TCA was chosen as the research subject, Fe/Ni bimetallic nanoparticles were employed as the reducing catalyst, ZIF-8@HMON as the catalytic carrier combined with Fe/Ni nanoparticles, and peroxymonosulfate (PMS) was introduced to construct the reducing-advanced oxidation synergistic system and investigated the effect of this system on the degradation performance and degradation pathway of TCA. Various characterization techniques, including TEM, SEM, XRD, FT-IR, XPS, BET, were employed to investigate the morphology, element composition and structure of composite materials analysis. Moreover, the conditions for TCA degradation can be optimized by changing the experimental environment. The results showed that 25 mg of composite catalyst (mole ratio Fe: Ni = 1:1) and 10 mg of PMS effectively degraded TCA within 20-80 mg/L range at pH = 3 and 55 °C, achieving maximum degradation within 20 min. Finally, the potential pathways of TCA degradation were analyzed using EPR and LC-MS, and the corresponding reaction mechanisms were proposed.

MRE11A: a novel negative regulator of human DNA mismatch repair.

BACKGROUND: DNA mismatch repair (MMR) is a highly conserved pathway that corrects DNA replication errors, the loss of which is attributed to the development of various types of cancers. Although well characterized, MMR factors remain to be identified. As a 3'-5' exonuclease and endonuclease, meiotic recombination 11 homolog A (MRE11A) is implicated in multiple DNA repair pathways. However, the role of MRE11A in MMR is unclear. METHODS: Initially, short-term and long-term survival assays were used to measure the cells' sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Meanwhile, the level of apoptosis was also determined by flow cytometry after MNNG treatment. Western blotting and immunofluorescence assays were used to evaluate the DNA damage within one cell cycle after MNNG treatment. Next, a GFP-heteroduplex repair assay and microsatellite stability test were used to measure the MMR activities in cells. To investigate the mechanisms, western blotting, the GFP-heteroduplex repair assay, and chromatin immunoprecipitation were used. RESULTS: We show that knockdown of MRE11A increased the sensitivity of HeLa cells to MNNG treatment, as well as the MNNG-induced DNA damage and apoptosis, implying a potential role of MRE11 in MMR. Moreover, we found that MRE11A was largely recruited to chromatin and negatively regulated the DNA damage signals within the first cell cycle after MNNG treatment. We also showed that knockdown of MRE11A increased, while overexpressing MRE11A decreased, MMR activity in HeLa cells, suggesting that MRE11A negatively regulates MMR activity. Furthermore, we show that recruitment of MRE11A to chromatin requires MLH1 and that MRE11A competes with PMS2 for binding to MLH1. This decreases PMS2 levels in whole cells and on chromatin, and consequently comprises MMR activity. CONCLUSIONS: Our findings reveal that MRE11A is a negative regulator of human MMR.

Perinatal exposure to traffic related air pollutants and the risk of infection in the first six months of life: a cohort study from a low-middle income country.

OBJECTIVE: There is limited study from low-and-middle income countries on the effect of perinatal exposure to air pollution and the risk of infection in infant. We assessed the association between perinatal exposure to traffic related air pollution and the risk of infection in infant during their first six months of life. METHODS: A prospective cohort study was performed in Jakarta, March 2016-September 2020 among 298 mother-infant pairs. PM2.5, soot, NOx, and NO2 concentrations were assessed using land use regression models (LUR) at individual level. Repeated interviewer-administered questionnaires were used to obtain data on infection at 1, 2, 4 and 6 months of age. The infections were categorized as upper respiratory tract (runny nose, cough, wheezing or shortness of breath), lower respiratory tract (pneumonia, bronchiolitis) or gastrointestinal tract infection. Logistic regression models adjusted for covariates were used to assess the association between perinatal exposure to air pollution and the risk of infection in the first six months of life. RESULTS: The average concentrations of PM2.5 and NO2 were much higher than the WHO recommended levels. Upper respiratory tract infections (URTI) were much more common in the first six months of life than diagnosed lower respiratory tract or gastro-intestinal infections (35.6%, 3.5% and 5.8% respectively). Perinatal exposure to PM2.5 and soot suggested increase cumulative risk of upper respiratory tract infection (URTI) in the first 6 months of life per IQR increase with adjusted OR of 1.50 (95% CI 0.91; 2.47) and 1.14 (95% CI 0.79; 1.64), respectively. Soot was significantly associated with the risk of URTI at 4-6 months age interval (aOR of 1.45, 95%CI 1.02; 2.09). All air pollutants were also positively associated with lower respiratory tract infection, but all CIs include unity because of relatively small samples. Adjusted odds ratios for gastrointestinal infections were close to unity. CONCLUSION: Our study adds to the evidence that perinatal exposure to fine particles is associated with respiratory tract infection in infants in a low-middle income country.

PMS2 mutation spectra in Norway and risk of cancer for carriers of pathogenic variants.

BACKGROUND: In Norway, we have offered testing of PMS2 since 2006, and have a large national cohort of carriers. The aim of this study was to describe all PMS2 variants identified, and to describe frequency, spectrum and penetrance of cancers in carriers of class 4/5 variants. METHODS: All detected PMS2 variants were collected from the diagnostic laboratories and reclassified according to ACMG criteria and gene specific guidelines. Data on variant, gender, cancer diagnosis, age at diagnosis, and age at last known follow-up was collected on all carriers of class 4/5 variants from electronic patient records. The Kaplan-Meier algorithm was used to calculate cumulative risk of any cancer, colorectal cancer and endometrial cancer. RESULTS: In total, 220 different PMS2 variants were detected. Twenty nine class 4/5 variants were identified in 482 carriers. The most common pathogenic variant was the founder mutation c.989-1G > T, detected in 204 patients from 58 families. Eighty seven out of 482 (18.0%) had been diagnosed with colorectal cancer, 10 of these (11.8%) before 40 years. Cumulative risk at 70 years in our cohort was 34.7% for colorectal cancer and 26.1% for endometrial cancer. CONCLUSIONS: After 15 years of genetic testing, 29 different class 4/5 variants have been detected in Norway. Almost half of Norwegian PMS2 carriers have the founder variant 989-1G > T. Penetrance of colorectal cancer in our cohort was moderate but variable, as 11.5% of those diagnosed were younger than 40 years.

Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes.

BACKGROUND: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. MATERIALS AND METHODS: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. RESULTS: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. CONCLUSIONS: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

Development and Characterization of Curcumin-Loaded TPGS/F127/P123 Polymeric Micelles as a Potential Therapy for Colorectal Cancer.

Colorectal cancer (CRC) is the third most prominent cancer worldwide, and the second leading cause of cancer death. Poor outcomes and limitations of current treatments fuel the search for new therapeutic options. Curcumin (CUR) is often presented as a safer alternative for cancer treatment with a staggering number of molecular targets involved in tumor initiation, promotion, and progression. Despite being promising, its therapeutic potential is hindered due to its hydrophobic nature. Hence, the ongoing development of optimal delivery strategies based on nanotechnology, such as polymeric micelles (PMs), to overcome issues in CUR solubilization and delivery to tumor cells. In this sense, this study aimed to optimize the development and stability of CUR-loaded P123:F127:TPGS PMs (PFT:CUR) based on the thin-film approach and evaluate their therapeutic potential in CRC. Overall, the results revealed that the solubility of CUR was improved when room temperature was used to hydrate the film. The PFT-CUR hydrated at room temperature presents an average hydrodynamic diameter of 15.9 ± 0.3 nm with a polydispersity index (PDI) of 0.251 ± 0.103 and a zeta potential of -1.5 ± 1.9 mV, and a 35.083 ± 1.144 encapsulation efficiency (EE%) and 3.217 ± 0.091 drug loading (DL%) were observed. To ensure the stability of the optimized PFT-CUR nanosystems, different lyophilization protocols were tested, the use of 1% of glycine (GLY) being the most promising protocol. Regarding the critical micellar concentration (CMC), it was shown that the cryoprotectant and the lyophilization process could impact it, with an increase from 0.064 mg/mL to 0.119 mg/mL. In vitro results showed greater cytotoxic effects when CUR was encapsulated compared to its free form, yet further analysis revealed the heightened cytotoxicity could be attributed to the system itself. Despite challenges, the developed CUR-loaded PM shows potential as an effective therapeutic agent for CRC. Nonetheless, the system must undergo refinements to enhance drug entrapment as well as improve overall stability.