Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy.

BACKGROUND: To report newly found TSPAN12 mutations with a unique form of familial exudative vitreoretinopathy (FEVR) and find out the possible mechanism of a repeated novel intronic variant in TSPAN12 led to FEVR. RESULTS: Nine TSPAN12 mutations with a unique form of FEVR were detected by panel-based NGS. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon11 hopping. Construction of wild-type and mutant TSPAN12 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of TSPAN12 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of TSPAN12 in cells transfected with the mutant vectors. CONCLUSIONS: Nine mutations in TSPAN12 gene are reported in 9 FEVR patients with a unique series of ocular abnormalities. The three novel TSPAN12 mutations trigger NMD would cause the decrease of TSPAN12 proteins that participate in biosynthesis and assembly of microfibers, which might lead to FEVR, and suggest that intronic sequence analysis might be a vital tool for genetic counseling and prenatal diagnoses.

Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes.

BACKGROUND: Mismatch repair (MMR) system is evolutionarily conserved for genome stability maintenance. Germline pathogenic variants (PVs) in MMR genes that lead to MMR functional deficiency are associated with high cancer risk. Knowing the evolutionary origin of germline PVs in human MMR genes will facilitate understanding the biological base of MMR deficiency in cancer. However, systematic knowledge is lacking to address the issue. In this study, we performed a comprehensive analysis to know the evolutionary origin of human MMR PVs. METHODS: We retrieved MMR gene variants from the ClinVar database. The genomes of 100 vertebrates were collected from the UCSC genome browser and ancient human sequencing data were obtained through comprehensive data mining. Cross-species conservation analysis was performed based on the phylogenetic relationship among 100 vertebrates. Rescaled ancient sequencing data were used to perform variant calling for archeological analysis. RESULTS: Using the phylogenetic approach, we traced the 3369 MMR PVs identified in modern humans in 99 non-human vertebrate genomes but found no evidence for cross-species conservation as the source for human MMR PVs. Using the archeological approach, we searched the human MMR PVs in over 5000 ancient human genomes dated from 45,045 to 100 years before present and identified a group of MMR PVs shared between modern and ancient humans mostly within 10,000 years with similar quantitative patterns. CONCLUSION: Our study reveals that MMR PVs in modern humans were arisen within the recent human evolutionary history.

Urea Synthesis via Coelectrolysis of CO2 and Nitrate over Heterostructured Cu-Bi Catalysts.

Electrocatalytic coupling of CO2 and NO3- to urea is a promising way to mitigate greenhouse gas emissions, reduce waste from industrial processes, and store renewable energy. However, the poor selectivity and activity limit its application due to the multistep process involving diverse reactants and reactions. Herein, we report the first work to design heterostructured Cu-Bi bimetallic catalysts for urea electrosynthesis. A high urea Faradaic efficiency (FE) of 23.5% with a production rate of 2180.3 µg h-1 mgcat-1 was achieved in H-cells, which surpassed most reported electrocatalysts in the literature. Moreover, the catalyst had a remarkable recycling stability. Experiments and density functional theory calculations demonstrated that introduction of moderate Bi induced the formation of the Bi-Cu/O-Bi/Cu2O heterostructure with abundant phase boundaries, which are beneficial for NO3-, CO2, and H2O activation and enhance C-N coupling and promote *HONCON intermediate formation. Moreover, favorable *HNCONH2 protonation and urea desorption processes were also validated, further explaining the reason for high activity and selectivity toward urea.

Pathogenic variants in human DNA damage repair genes mostly arose in recent human history.

BACKGROUND: Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes. METHODS: We identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis. RESULTS: Our phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. CONCLUSIONS: Our study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

Mutations in ADAMTSL4 cause a unique form of autosomal-recessive congenital ectopia lentis.

Several unique mutations of ADAMTSL4 leading to congenital ectopia lentis (CEL) have been previously reported by our team. The purpose of this study is to find out the possible mechanism of a recurrent novel intronic variant in ADAMTSL4 led to CEL. Twelve novel ADAMTSL4 mutations with a unique form congenital ectopic lentis were detected previously by panel-based NGS. Genetic analysis verified a novel heterozygous ADAMTSL4 variation c.2177+4A > G on Intron 11 in two unrelated patients with iris and lens abnormalities. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon 11 skipping. Construction of wild-type and mutant ADAMTSL4 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of ADAMTSL4 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of ADAMTSL4 in cells transfected with the mutant vectors. 12 novel mutations in ADAMTSL4 gene have been previously reported by our team in 6 CEL patients with a unique series of ocular abnormalities. The recurrent novel ADAMTSL4 mutation c.2177+4A > G triggering the splicing mode of Exon 11 skipping and NMD would cause the decrease of ADAMTSL4 proteins that participate in biosynthesis and assembly of microfibers, which might lead to CEL, and suggest that sequencing of certain intronic splicing varition might be a vital tool for genetic counseling and prenatal diagnoses.

Preliminary investigation of MMP8 (rs11225395) and MMP9 (rs3787268) polymorphisms association with breast cancer risk in pashtun women of Pakistan.

BACKGROUND: Single Nucleotide polymorphisms (SNPs) in MMP8 and MMP9 have been widely associated with breast cancer risk in different ethnicities with inconsistent results. There is no such study conducted so far in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. Therefore, this study was conducted to check MMP8 (rs11225395) and MMP9 (rs3787268) polymorphism with breast cancer risk in the selected population. METHODS: This study, consisting of 300 breast cancer patients and 168 gender and age-matched healthy controls was subjected to confirm MMP8 and MMP9 polymorphisms. Clinicopathological data and blood samples were taken from all the participants. DNA was extracted and SNPs were confirmed using the T-ARMS-PCR protocol. RESULTS: Based on our study results, significant associations were observed between the MMP8 rs11225395 risk allele (G) and increased breast cancer risk, with the G allele frequency higher in patients (65%) compared to controls (51%) (OR = 1.752, 95% CI = 1.423-3.662, p = 0.002). Genotypes GG (OR = 4.218, p = 0.005) and AG (OR = 7.286, p = 0.0001) of MMP8 rs11225395 were also significantly associated with elevated breast cancer risk. Similarly, MMP9 rs3787268 exhibited a higher frequency of the risk allele (A) in breast cancer cases (81%) compared to controls (41%), correlating strongly with increased risk (OR = 6.320, p = 0.0001). Genotypes AA (OR = 14.500, p = 0.0001) and AG (OR = 2.429, p = 0.077) of MMP9 rs3787268 containing the risk allele showed significant associations with heightened breast cancer risk. Subgroup analyses based on age, disease progression, tumor size, and grade revealed noteworthy associations for both MMP8 rs11225395 and MMP9 rs3787268. MMP8 rs11225395 genotypes displayed significant correlations with age (p = 0.066), disease progression (p = 0.0001), larger tumor size (p = 0.005), and higher tumor grade (p = 0.006). Similarly, MMP9 rs3787268 genotypes were significantly associated with age (p = 0.001), disease progression (p = 0.010), larger tumor size (p = 0.018), and higher tumor grade (p = 0.037). Logistic regression analyses further underscored these genetic variants' potential role as biomarkers in breast cancer, particularly in relation to specific hormone receptor statuses such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) positivity. CONCLUSION: The results revealed significant associations between the mutant alleles and genotypes of MMP8 (rs11225395) and MMP9 (rs3787268) with increased breast cancer risk in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. However, more investigation will be required on large data sets to confirm the selected SNPs and other SNPs in the selected and other related genes with the risk of breast cancer.

Association analysis of miRNA-146a and miRNA-196a polymorphism with breast cancer risk in Khyber Pakhtunkhwa, Pakistan: a preliminary study.

BACKGROUND: microRNAs (miRNAs) are small, noncoding RNA molecules, functioning either as oncogenes or tumor suppressor genes. SNPs in miRNAs might modify the expression of genes associated with miRNAs, enhancing susceptibility to breast cancer. Both miRNA-146a (rs2910164) and miRNA-196a (rs11614913) are identified and significantly associated with breast cancer risk in several ethnicities, but remains unexplored in Khyber Pakhtunkhwa population of Pakistan. METHODS: This study was aimed to check the relation of selected SNPs with breast cancer risk. The research cohort included 100 breast cancer patients and 100 healthy controls. All the participants were subjected for DNA extraction followed by T-ARMS PCR and gel electrophoresis. RESULTS: The results revealed a strong association between risk allele (G) of miRNA-146a and increased risk of breast cancer (OR = 2.04, P = 0.0006). Similarly, heterozygous and mutant genotypes also indicated high risk and significant association with breast cancer risk (CG; OR = 0.51, 9 P = 0.0001) (GG; OR = 3.76, P = 0.04). However, risk allele (T) of miRNA-196a (rs11614913) failed to exhibit significant association with breast cancer risk (OR = 0.92 P = 0.68). Similarly, the heterozygous and mutant genotype did not show significant association with breast cancer risk (CT; OR = 0.52, P = 0.125 (TT; OR = 0.88, P = 0.84). Furthermore, miRNA-146a (rs2910164) and miRNA-196a (rs11614913) polymorphisms exhibited non-significant associations with family history (P = 0.34, P = 0.77), PR status (P = 0.310, P = 0.397), ER status (P = 0.992, P = 0.981), nodal status (P = 0.86, P = 0.90), and menstrual status (P = 0.97, P = 0.09). Notably, miRNA-196a showed a significant association with the metastasis group (P = 0.010) and cancer stages (P = 0.047). CONCLUSIONS: In conclusion, this study highlights the association of miRNA-146a (rs2910164) polymorphism with breast cancer risk but suggested non-significant association of miRNA-196a (rs11614913) with breast cancer risk. However, these findings need to be confirmed through larger data set for more accurate result.

Application of sutureless corneal incision for patients with congenital ectopia lentis - Is it feasible, effective and safe?

Purpose: To compare the clinical outcomes, feasibility, and safety between groups with sutured and sutureless wound closure in congenital ectopia lentis (CEL) patients. Methods: Patients with CEL who received phacoemulsification combined with intrascleral fixation of capsular hook (CH) and implantation of capsular tension ring (CTR) and in-the-bag intraocular lens (IOL) were included in this study. Results: A total of 68 eyes of 34 patients aged 18 years or younger were enrolled in this study. Incisions of 21 patients (34 eyes) did not require sutures while sutures were applied in 21 patients (34 eyes). Postoperative uncorrected distance visual acuity, best corrected distance visual acuity and intraocular pressure measurements were comparable on follow-up visits (P > 0.05). The magnitude of surgically induced astigmatism was significantly greater (P = 0.001) in the suture group (Median: 0.47; IQ: 1.63, 2.97) than in the sutureless group (Median: 0.88; IQ: 0.63, 1.35). No cases of endophthalmitis and retinal detachment were found postoperatively in either group, while suture-related complications were observed in the sutured group, including loose suture with discomfort in 5 (14.71%) eyes, loose suture with mucus infiltration in 3 (8.82%) eyes. In total, 22 sutures (64.71%) of 34 eyes required removal. Conclusions: Sutureless clear corneal incision in CEL patients can achieve satisfactory clinical results comparable to sutured wound closure in terms of the efficacy and safety. Advantages of this approach are the reduced risk of suture-related complications, no need for additional surgery under general anesthesia for suture removal, and less cost.

Use of period analysis to provide a timely assessment of 5-year relative survival for pancreatic cancer patients from Taizhou, eastern China.

Assessing long-term tumor survival rates is crucial for evaluating the effectiveness of tumor treatment and burden. However, timely assessment of long-term survival in patients with pancreatic cancer is lagging in China. In this study, we applied period analysis to estimate the long-term survival of pancreatic cancer patients using data from four population-based cancer registries in Taizhou city, eastern China. A total of 1121 patients diagnosed with pancreatic cancer between 2004 and 2018 were included. We assessed the 5-year relative survival (RS) using period analysis and further stratified by sex, age at diagnosis, and region. The 5-year RS during 2014-2018 overall reached 18.9% (14.7% for men and 23.3% for women, respectively). A decrease of the 5-year RS from 30.3% to 11.2% was observed in four diagnostic age gradients (< 55, 55-64, 65-74, and > 74 years age groups). The 5-year RS was higher in urban (24.2%) than in rural (17.4%) areas. Moreover, the 5-year RS of pancreatic cancer patients showed an overall increasing trend for the three periods (2004-2008, 2009-2013, and 2014-2018). Our study, using period analysis for the first time in China, provides the latest estimates of the survival of patients with pancreatic cancer, which provides essential evidence for the prevention and intervention of pancreatic cancer. The results also indicate the importance of further applications of the period analysis for more up-to-date and accurate survival estimates.

Biallelic ADAMTSL4 variants in a Chinese cohort of congenital ectopia lentis: Implications for genotype-phenotype relationships.

ADAMTSL4 variants are one of the common causes of congenital ectopia lentis (EL), reported ocular comorbidities of which include iris anomalies, cataract, and glaucoma. However, a genotype-phenotype correlation has not been established. Potentially pathogenic ADAMTSL4 variants were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing followed by multiple bioinformatics analyses. The genotype-phenotype correlation was assessed via a systematic review of ADAMTSL4 variants within our data and those from the literature. A total of 12 variants of ADAMTSL4, including seven frameshift variants, one nonsense variant, two splicing variants, and two missense variants, were found in nine probands. Combing genetic and clinical information from 72 probands in the literature revealed 37 ADAMTSL4 variants known to cause EL, and the ethnic difference was prominent. The lens was inclined to dislocate inferior temporally (22, 27.16%), while the pupil was always located oppositely (9, 81.82%). Several anterior segments anomalies were identified, including ectopia pupillae (15, 18.52%), persistent pupillary membrane (9, 11.10%), poor pupil dilation (4, 30.8%), cataract (13, 24.10%), and glaucoma (8, 13.33%). Genotype-phenotype analysis revealed that truncation variants had higher risks of combined iris anomalies, including either ectopia pupillae or a persistent pupillary membrane (p = 0.007). The data from this study not only extend our knowledge of the ADAMTSL4 variant spectrum but also suggest that deleterious variants of ADAMTSL4 might be associated with severe ocular phenotypes.

Lipid Droplet-Associated Proteins in Cardiomyopathy.

BACKGROUND: The heart requires a high rate of fatty-acid oxidation (FAO) to meet its energy needs. Neutral lipids are the main source of energy for the heart and are stored in lipid droplets (LDs), which are cytosolic organelles that primarily serve to store neutral lipids and regulate cellular lipid metabolism. LD-associated proteins (LDAPs) are proteins either located on the surface of the LDs or reside in the cytosol and contribute to lipid metabolism. Therefore, abnormal cardiac lipid accumulation or FAO can alter the redox state of the heart, resulting in cardiomyopathy, a group of diseases that negatively affect the myocardial function, thereby leading to heart failure and even cardiac death. SUMMARY: LDs, along with LDAPs, are pivotal for modulating heart lipid homeostasis. The proper cardiac development and the maintenance of its normal function depend largely on lipid homeostasis regulated by LDs and LDAPs. Overexpression or deletion of specific LDAPs can trigger myocardial dysfunction and may contribute to the development of cardiomyopathy. Extensive connections and interactions may also exist between LDAPs. Key Message: In this review, the various mechanisms involved in LDAP-mediated regulation of lipid metabolism, the association between cardiac development and lipid metabolism, as well as the role of LDAPs in cardiomyopathy progression are discussed.

Comparison of Accuracy in Keratometries Measured by Different Camera Devices for Predicting the Intraocular Lens Power in Lens-Dislocated Patients.

INTRODUCTION: This is a cross-sectional cohort study focused on assessing the influence of ocular biometric parameters of different camera devices for accurately predicting the intraocular lens (IOL) power in the congenital ectopia lentis (EL) patients. METHODS: This study includes a total of 91 eyes of 60 patients with congenital EL from June 2018 to April 2021. All patients underwent lens subluxation surgery with Cionni modified capsular tension rings (MCTR) implantation. Ocular parameters measured by partial coherence interferometry (IOLMaster 700, Carl Zeiss Meditec AG, Jena, Germany) and rotating Scheimpflug camera (Pentacam HR system, Oculus Optikgeräte GmbH, Wetzlar, Germany) were acquired from the database. The authenticity of the different keratometries (K) were analyzed by comparing the prediction error in spherical equivalent under controlled formula SRK/T, Haigis, and after Wang-Koch (WK) adjustment. RESULTS: We observed significant greater K values were obtained in IOLMaster than Pentacam, resulting in more significant hyperopia error while calculating SRK/T. The IOL power calculated with the total corneal refractive power (TCRP) from Pentacam revealed the highest prediction accuracy, indicating that TCRP is the closest to the actual refractive power of the cornea. However, in an exceptional case for long eye patients, total keratometry from IOLMaster was better recommended when using formula Haigis with WK adjustment. CONCLUSIONS: For most instances, TCRP is the best-recommended source of K value while calculating IOL power for EL patients. However, the total keratometry from IOLMaster preferably fits for long eye patients, who require WK adjustment for Haigis formula.

Zonular defects in loxl1-deficient zebrafish.

BACKGROUND: To investigate the roles of the lysyl oxidase-like 1 (loxl1) gene in zebrafish eye development and the potency of loxl1 deficiency in mimicking the ocular manifestations of exfoliation syndrome (XFS). METHODS: CRISPR/Cas9 technology was used to generate a frameshift coding deletion in zebrafish loxl1. Expression profiles and ocular manifestations of the wildtype, heterozygous mutant (loxl1+/- ) and homozygous mutant (loxl1-/- ) zebrafish were analysed in a range of developmental stages from zebrafish larvae to dissected adult zebrafish eyes. RESULTS: The loxl1 deficiency caused zonular bundling disorders in juvenile zebrafish and accumulation of pearl-like particles adhering to the adult zebrafish zonule. The bundles appeared to lack form and were thinner in both loxl1+/- and loxl1-/- zebrafish compared with the wildtype (p < 0.01 for all Bonferroni post-hoc analyses). The zonule of loxl1-/- zebrafish appeared stretched, ragged and torn, with isolated fibres also detected. The particles in loxl1-/- zebrafish were more numerous (counts: 92.33 ± 10.02/100 µm2 vs. 58.33 ± 5.03/100 µm2 , p = 0.006), but smaller in size (diameter: 0.21 ± 0.03 µm vs. 0.43 ± 0.04 µm, p = 0.002) compared with those in loxl1+/- . Transmission electron microscopy revealed thinning or even loss of elastic lamina in loxl1+/- Bruch's membrane (BM) (thickness of elastic lamina: 92.94 ± 18.19 nm in the wildtype vs 35.65 ± 14.76 nm in loxl1+/- , p = 0.003). The breakage of BM was observed in loxl1-/- . CONCLUSIONS: The loxl1-/- zebrafish is a promising animal model of XFS zonular pathology.

Correlation between FBN1 mutations and ocular features with ectopia lentis in the setting of Marfan syndrome and related fibrillinopathies.

Mutations of fibrillin-1 (FBN1) have been associated with Marfan syndrome and pleiotropic connective tissue disorders, collectively termed as "type I fibrillinopathy". However, few genotype-phenotype correlations are known in the ocular system. Patients with congenital ectopia lentis (EL) received panel-based next-generation sequencing, complemented with multiplex ligation-dependent probe amplification. In a total of 125 probands, the ocular phenotypes were compared for different types of FBN1 mutations. Premature termination codons were associated with less severe EL and a thinner central corneal thickness (CCT) than the inframe mutations. The eyes of patients with mutations in the C-terminal region had a higher incidence of posterior staphyloma than those in the middle and N-terminal regions. Mutations in the TGF-ß-regulating sequence had larger horizontal corneal diameters (white-to-white [WTW]), higher incidence of posterior staphyloma, but less severe EL than those with mutations in other regions. Mutations in the neonatal region were associated with thinner CCT. Longer axial length (AL) was associated with mutations in the C-terminal region or TGF-ß regulating sequence after adjusting for age, EL severity, and corneal curvature radius. FBN1 genotype-phenotype correlations were established for some ocular features, including EL severity, AL, WTW, CCT, and so forth, providing novel perspectives and directions for further mechanistic studies.

Incidence, mortality and survival in malignant pleural mesothelioma before and after asbestos in Denmark, Finland, Norway and Sweden.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but fatal cancer, which is largely caused by exposure to asbestos. Reliable information about the incidence of MPM prior the influence of asbestos is lacking. The nationwide regional incidence trends for MPM remain poorly characterized. We use nationwide MPM data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to assess incidence, mortality and survival trends for MPM in these countries. METHODS: We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1958 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization. RESULTS: The lowest incidence that we recorded for MPM was 0.02/100,000 for NO women and 0.05/100,000 for FI men in 1953-57, marking the incidence before the influence of asbestos. The highest rate of 1.9/100,000 was recorded for DK in 1997. Female incidence was much lower than male incidence. In each country, the male incidence trend for MPM culminated, first in SE around 1990. The regional incidence trends matched with earlier asbestos-related industrial activity, shipbuilding in FI and SE, cement manufacturing and shipbuilding in DK and seafaring in NO. Relative 1-year survival increased from about 20 to 50% but 5-year survival remained at or below 10%. CONCLUSION: In the Nordic countries, the male incidence trends for MPM climaxed and started to decrease, indicating that the prevention of exposure was beneficial. Survival in MPM has improved for both sexes but long-term survival remains dismal.

Evaluation of the B/F Ratio Distribution of Cataract Patients Without Corneal Abnormalities and Its Effect on Ocular Parameters.

PURPOSE: To evaluate the distribution of the posterior-anterior corneal radius ratio (B/F ratio; posterior corneal radius/anterior corneal radius) in patients without corneal abnormalities, and to investigate which parameters affect this ratio. METHODS: Five thousand eyes from 5,000 patients who underwent cataract surgery were recruited to this study. We explored the linear relationship between B/F ratio and 13 variables using Principal Component-Multivariate Linear Regression Analysis. RESULTS: The B/F ratio was negatively correlated with the difference between simulated keratometry (SimK) and true net power (TNP), central corneal thickness, spherical aberration (SA), and posterior corneal astigmatism and positively correlated with posterior corneal radius, corneal posterior surface, axial length (AL) and anterior corneal radius. Several variables (central corneal thickness, difference between SimK and TNP and asphericity coefficient (Q-value) of the posterior corneal surface) had the highest loading on the final score. B/F ratio reflects the refractive state and anatomical structure of the cornea: thus, higher B/F ratios were associated with larger posterior corneal surface curvature radius, longer axial length, thinner central corneal thickness, lower high order aberrations of the cornea and SA, and the numerical difference between simK and TNP gradually reduced. In clinical practice, for patients with lower B/F ratio, special care should be taken in the choice of system used for intraocular lens (IOL) measurements.

Analysis of Axial Length in Young Patients with Marfan Syndrome and Bilateral Ectopia Lentis by Z-Scores.

INTRODUCTION: Marfan syndrome (MFS) is characterized by ectopia lentis (EL) and elongated axial length (AL). The characteristics of AL in young patients with MFS and bilateral EL before the lens surgery are not fully understood. METHODS: This study reviewed MFS patients under 20 years old with bilateral EL from January 2015 to October 2020. The Z-scores were introduced in terms of the number of standard deviations from the mean of age-matched normative data. Using Z-scores, the distribution of AL and influence factors were evaluated. The correlations between AL and other biometrics were analyzed. RESULTS: We reviewed 183 patients and enrolled both eyes. The mean age was 8.44 ± 4.69 years. About 36% of the patients were children under 6 years old. The median AL increased from 23.16 mm under 5 years old to 26.20 mm in the 16-20 age group, and when plotted, the trend presented a logarithmic curvature (R2 = 0.145, p < 0.001). The median Z-AL score was 1.24. One-third of eyes had Z-score <0. About 20% of the patients had AL difference over 1 mm between the right and left eyes, and the right one had longer Z-AL scores (p = 0.013). The eye complicated with megalocornea (10, 7.04%) had larger Z-AL scores (4.72 ± 3.51 vs. 1.10 ± 2.25, p = 0.002). A positive correlation was found between Z-AL and Z-corneal curvature radius (r = 0.265, p < 0.001). CONCLUSION: Young patients with bilateral EL but small AL should not be excluded from MFS without systematic examination. The age-adjusted Z-score will facilitate further study of the individual variations in AL across different ages.

Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China.

DNA mismatch repair (MMR) genes play an important role in maintaining genome stability. Germline mutations in MMR genes disrupt the mismatch repair function and cause genome instability. Carriers with MMR germline mutations are more likely to have MMR deficiency and microsatellite instability (MSI) than non-carriers and are prone to develop colorectal cancer (CRC) and extracolorectal malignancies, known as Lynch syndrome (LS). MMR gene testing for suspected mutation carriers is a reliable method to identify the mutation types and to discover mutation carriers. Given that carriers of MMR germline mutations have a higher risk of LS-related cancers (LS-RC) and a younger age at onset than non-carriers, early surveillance and regular screening of relevant organs of carriers are very important for early detection of related cancers. This review mainly focuses on the general status of MMR carriers, the approaches for early detection and screening, and the surveillance of MMR mutation carriers in China. Population screening of MMR germline mutation carriers in China will be helpful for early detection, early diagnosis and treatment of MMR mutation carriers, which may improve the 5-year survival, and reduce mortality and incidence rate in the long term.

A rare large duplication of MLH1 identified in Lynch syndrome.

BACKGROUND: The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. METHODS: In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. RESULTS: Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. CONCLUSIONS: We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

Assessment of long-term survival of cancer patients using cancer registry data from eastern China: Period analysis is superior to traditional methods.

We aimed to provide a systematical evaluation of the performance of period analysis compared to traditional cohort and complete methods, using cancer registry data from Taizhou, eastern China. Overall, 5-year relative survival (RS) estimate was calculated using cohort analysis, complete analysis and period analysis, respectively; further analyses were stratified by sex, region, age at diagnosis and cancer sites. Deviation value (DV), defined as the deviation between the estimated 5-year RS obtained from each method and the observed actual survival, was calculated to evaluate the accuracy of each method. Overall, 5-year RS derived by period analysis were much closer to the observed actual survival (51.4%), compared to those by complete and cohort methods, with the estimates of 48.7% (DV: -2.7%), 43.2% (DV: -8.2%) and 36.3% (DV: -15.1%), respectively. Further stratifications by sex, age at diagnosis, region and cancer sites also supported period analysis provided more precise estimates, compared to complete and cohort methods. We found, for first time systematically using cancer registry data from eastern China, period analysis provided more up-to-date precise estimates of long-term survival for overall and stratifications by sex, age at diagnosis, region and cancer sites, compared to traditional cohort and complete methods. Nevertheless, further investigations using large cancer registry data across China are warranted for the widespread use of period analysis in China.