A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.

New proposal to revise the classification for squamous cell carcinoma of the external auditory canal and middle ear.

BACKGROUND: The prognosis of patients with advanced squamous cell carcinoma of the external auditory canal and middle ear has been improved by advances in skull base surgery and multidrug chemoradiotherapy during the last two decades. METHODS: Ninety-five patients with squamous cell carcinoma of the external auditory canal and middle ear who were treated between 1998 and 2017 were enrolled. The number of patients with tumour stages T1, T2, T3 and T4 was 15, 22, 24 and 34, respectively. Oncological outcomes and prognostic factors were retrospectively investigated. RESULTS: Among patients with T4 disease, invasion of the brain (p = 0.024), carotid artery (p = 0.049) and/or jugular vein (p = 0.040) were significant predictors of poor prognosis. The five-year overall survival rate of patients with at least one of these factors (T4b) was significantly lower than that of patients without these factors (T4a) (25.5 vs 65.5 per cent, p = 0.049). CONCLUSION: It is proposed that stage T4 be subclassified into T4a and T4b according to the prognostic factors.

Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats.

AIM: Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344-derived genome. METHODS: Congenic animals were produced by introgressing F344-derived Dmo1 alleles into the OLETF rat. Congenic animals of the fourth generation (BC4) were intercrossed to obtain F1 animals (BC4:F1). Animals of the next generation, BC4:F2, were used for this study. We used 23 BC4:F2 males harbouring homozygous replacement of the OLETF Dmo1 region with the F344-derived genome. Seven animals with OLETF-derived Dmo1 alleles were used as controls. RESULTS: Dmo1-F344/F344 congenic rats showed significant decreases in body weight, abdominal fat weight, serum triacylglycerols, total cholesterol, food consumption and blood glucose after glucose loading (13%, 39%, 45%, 27%, 18% and 27% respectively; p < 0.05) compared with Dmo1-OLETF/OLETF animals. Furthermore, histopathological analysis of the kidney showed that mesangial sclerosis, hyalin deposits and deposition of PAS-positive substance were significantly lower in Dmo1-F344/F344 animals (p < 0.05). CONCLUSION: Improvements in metabolic parameters and histopathological scores show that correction of the Dmo1 genetic pathway in the diabetic and mildly obese OLETF rat strain produces wide-ranging therapeutic effects. Thus, this pathway might represent a new drug target also applicable to humans.

Estrogen receptor levels and lipid peroxidation in hepatocellular carcinoma with hepatitis C virus infection.

AIMS/BACKGROUND: Our preliminary studies showed that estradiol suppresses hepatic carcinogenesis and fibrogenesis in animal models. Hepatic estrogen receptors (ERs) medicate estradiol action in the liver. This study was performed to assess possible implications of menopause and hepatic ER levels for the development of cirrhosis with hepatocellular carcinoma (HCC). METHODS: One thousand, one hundred and ninety-nine consecutive HCC patients with hepatitis C virus (HCV)-related cirrhosis were divided into two groups, based on a menopausal age of 49 years. Liver tissues were obtained during surgical resection of HCC and metastatic liver tumor. RESULTS: The proportion of females among the HCC subjects < or =49 years of age was significantly lower (15.0%) than was the proportion of females among subjects >49 years of age (29.8%). Univariate analysis showed that HCV-related cirrhotic patients who developed HCC were more likely to have low hepatic levels of ER and copper-zinc superoxide dismutase (CuZn-SOD) protein and a high hepatic level of a lipid peroxidation product, malondialdehyde (MDA). Logistic regression identified age greater than 49 years (odds ratio [OR]: 7.9, 95% confidence interval [CI]: 2.8-21.3), male sex (OR: 3.5, 95% CI: 1.3-10.2), a decreased ER level (OR: 16.8, 95% CI: 7.3-34.6), and an increased MDA (OR: 8.3, 95% CI: 2.8-24.0) as the variables independently associated with the development of HCC in HCV-infected patients with cirrhosis. ER level was significantly correlated with CuZn-SOD level (r=0.583) and was inversely proportional to MDA level (r=-0.553). The study also showed that ER levels in the cirrhotic livers from premenopausal females were significantly higher than in male cirrhotic livers. CONCLUSIONS: These findings suggest that increased lipid peroxidation and impaired SOD function in the liver may be associated with decreased hepatic ER levels in HCV-infected patients with cirrhosis and HCC, and that HCV-related cirrhotic women before menopause might have the ability to protect against developing HCC via hepatic ER.

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain.

Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.

Molecular cloning of human squamous cell carcinoma antigen 1 gene and characterization of its promoter.

The squamous cell carcinoma antigen (SCCA) serves as a serological marker for squamous cell carcinomas. Molecular cloning of the SCCA genomic region has revealed the presence of two tandemly arrayed genes, SCCA1 and SCCA2, which are 95% identical in nucleotide sequence. SCCA1 is a papain-like cysteine proteinase inhibitor, while SCCA2 is a chymotrypsin-like serine proteinase inhibitor. We analyzed here the sequence and the promoter activity of the 5'-flanking region of the SCCA1 gene. Deletion analysis of SCCA1 and SCCA2 promoter identified a 471-bp core promoter region upstream of the transcription start site. The transcriptional activity of SCCA1 promoter was up-regulated in squamous cell carcinoma cells, compared with keratinocyte and adenocarcinoma cells. The ratios of SCCA1 to SCCA2 promoter activity in squamous cell carcinoma, keratinocyte and adenocarcinoma cells were respectively 1.6, 5.3 and 2.8. Position -50 of SCCA1 and SCCA2 promoters played an important role in determining the promoter activities of SCCA1 and SCCA2. These findings suggest that the transcriptional regulation of SCCA1 and SCCA2 might differ among squamous cell carcinoma, keratinocyte and adenocarcinoma cells, and that SCCA1 promoter might be a potential target of gene therapy for squamous cell carcinoma.

Single-allele correction of the Dmo1 locus in congenic animals substantially attenuates obesity, dyslipidaemia and diabetes phenotypes of the OLETF rat.

1. Whole-genome scans have identified Dmo1 as a major quantitative trait locus for dyslipidaemia and obesity in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. 2. We have produced congenic rats for the Dmo1 locus through successive back-cross breeding with diabetic OLETF rats. Marker-assisted speed congenic protocols were applied to efficiently transfer chromosomal segments from non-diabetic Brown Norway (BN) rats into the OLETF background. 3. In the fourth generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. 4. We have concluded that Dmo1 primarily affects lipid homeostasis, obesity control and/or glucose homeostasis at fasting and is secondarily involved in glucose homeostasis after loading. 5. The results of the present study show that single-allele correction of a genetic defect of the Dmo1 locus can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.

Quantitative trait loci for lipid metabolism in the study of OLETF x (OLETF x Fischer 344) backcross rats.

1. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a model of type II diabetes with accompanying dyslipidaemia and obesity. 2. To define chromosomal intervals associated with obesity (abdominal fat weight and plasma leptin levels), dyslipidaemia (plasma triglyceride, cholesterol and free fatty acids) and hyperglycaemia (plasma glucose levels), we have performed genome-wide quantitative traits loci (QTL) analyses of 115 male OLETF x (OLETF x Fischer 344) backcross animals at 16 weeks of age. 3. The Diabetes Mellitus OLETF type I (Dmo1) locus on rat chromosome 1 showed statistically significant involvement in elevations of plasma levels of triglycerides (P = 4.87 x 10(-6) at D1Rat90) and total cholesterol (P = 1.16 x 10(-5) at D1Rat306). 4. No other loci produced significant linkage to these observed phenotypes. 5. These analyses have confirmed the importance of Dmo1 in lipid homeostasis at younger ages as well as during overt diabetes, which appears later. Thus, alterations at the Dmo1 locus are a major risk factor for pathogenesis in the strain, a finding that agrees with physiological studies that indicate a role for dyslipidaemia in the type II diabetic syndrome of OLETF rats.

In situ characterization of dendritic cells occurring in the islets of nonobese diabetic mice during the development of insulitis.

Type 1 diabetes mellitus in nonobese diabetic (NOD) mice, a well-known model of human type 1 diabetes, has been considered to be caused by the destruction of insulin-producing beta cells in the islets of the pancreas by self-reactive T cells. Antigen-presenting cells like dendritic cells (DCs) and macrophages are expected to be involved in the processes from their role in generating regulatory or effector T cells. These immunohistochemical studies revealed that CD11c-positive DCs already appeared in the islets of NOD mice as early as 4 weeks old when lymphocytes were not yet infiltrated in the islet, and thus insulitis was not developed. DCs were first observed to locate around swollen parainsular vessels. From age 7 weeks onward to age 13 weeks, more DCs were present in parainsular areas where lymphocytes had also accumulated, and the number of DCs in the islets as well as lymphocytes increased. However, at the end stage of insulitis from age approximately 17 weeks onward, the number of DCs in the islets decreased. In contrast, accumulation of DCs in the para- and periislets was not observed in 7- and 17-week-old ICR female mice that do not develop type 1 diabetes. Double-staining studies using confocal laser scanning microscopy showed that the CD11c-positive DCs coexpress both major histocompatibility (MHC) class II and costimulatory molecules, CD80 and CD86. Electron-microscopy studies further demonstrated that cell bodies and processes of the DCs make close contact with lymphocytes. These results suggest that DCs infiltrated into the pancreatic islets are capable of stimulating T cells by the MHC class II-antigenic peptide complex, together with costimulatory molecules, which eventually lead to the beta-cell destruction in NOD mice.

Transfer of dendritic cells (DC) ex vivo stimulated with interferon-gamma (IFN-gamma) down-modulates autoimmune diabetes in non-obese diabetic (NOD) mice.

The NOD mouse has been used to explore the many features of insulin-dependent diabetes mellitus (IDDM) that is caused by the destruction of insulin-producing beta cells in the islets of Langerhans of the pancreas. Self-reactive T cells have been considered to mediate IDDM in the NOD mouse, and antigen-presenting cells like DC and macrophages are expected to be involved in the processes from their role in generating regulatory or effector T cells. The present study shows that transfer of IFN-gamma-stimulated DC of the NOD or ICR mouse into the NOD mouse did not accelerate IDDM onset but afforded long-lasting protection against clinical and histological signs of IDDM in the recipient mice. The anti-diabetogenic ability was unique to IFN-gamma-stimulated DC when compared with unstimulated DC. A considerable proportion of the injected IFN-gamma-stimulated DC was demonstrated to migrate into the pancreas and its associated lymphoid tissues, suggesting the DC exert their anti-diabetogenic effects there. These findings suggest that development of autoimmune diabetes in the NOD mouse is under the control of DC, and that IDDM onset could be controlled by appropriately manipulating DC systems in vivo, which may open the gate for the therapeutic application of ex vivo-conditioned DC to human IDDM.

Brugada syndrome associated with an autonomic disorder.

A 44 year old man with Brugada syndrome and ventricular fibrillation had an autonomic disorder, shown by spectral analysis of heart rate variability and 123I-MIBG myocardial scintigraphy. Periodic variation of the ST segments was detected by Holter ECG. Increased high frequency power (0.15-0.40 Hz), an index of parasympathetic nerve activity, was observed just before ST segment elevation. In addition, local dysfunction of sympathetic nerves in the left ventricle was detected by 123I-MIBG myocardial scintigraphy. Unbalanced autonomic nerve function plays an important role in inducing Brugada-type ECG signs.

Identification and chromosomal assignment of USP1, a novel gene encoding a human ubiquitin-specific protease.

We have cloned a novel gene encoding a human ubiquitin-specific protease (USP1). The product, which consists of 785 amino acids with a deduced molecular mass of 88.2 kDa, possesses His and Cys domains that are highly conserved in all members of the ubiquitin-specific processing (UBP) family of proteases. Recombinant USP1 protein showed genuine UBP activity, correctly cleaving Ub-beta-galactosidase to produce ubiquitin and beta-galactosidase. Chromosomal mapping by fluorescence in situ hybridization and radiation hybrid analyses localized the USP1 gene to the p31.3-p32.1 band of chromosome 1. As losses of heterozygosity or amplifications have been observed in the distal region of the short arm of chromosome 1 in some neuroblastomas, breast cancers, and pancreatic adenocarcinomas, the USP1 gene may be a candidate for either the tumor-suppressive or the oncogenic activities associated with that chromosomal region.

Echocardiographic assessment of right atrial function in patients with myocardial infarction with reference to obstructive lesions of the coronary arteries.

We assessed the relationship between right atrial (RA) function and obstructive lesions of the coronary arteries in 29 patients with recent or old myocardial infarction (MI). Patients were divided into 3 groups according to the location of obstructions as follows: obstruction at the proximal right coronary artery (segments 1 and 2) (RCA proximal group, n=9); obstruction at the distal RCA (segments 3 and 4) (RCA distal group, n=6); and obstruction at the left anterior descending coronary artery (LCA group, n=14). The RA volume and the fractional change in the RA area during atrial contraction (RA %AC) were evaluated by apical 2-dimensional echocardiography. The right ventricular (RV) end-diastolic pressure (RVEDP) was measured in 4 patients in the RCA proximal group and 4 patients in the LCA group. The ejection fraction of the right ventricle (RVEF) was measured by radionuclide angiography or 2-dimensional echocardiography in 7 patients in the RCA proximal group, 5 patients in the RCA distal group, and 7 patients in the LCA group. The RVEF tended to be lower in the RCA proximal group than in the RCA distal and LCA groups. The RA volume was significantly greater in the RCA proximal group than in the LCA group. The RA %AC was significantly smaller in the RCA proximal group than in the RCA distal and LCA groups. There were no significant differences in the early diastolic RV inflow velocity among groups, but the late diastolic RV inflow velocity was significantly lower in the RCA proximal group than in the RCA distal and LCA groups. There was no significant difference in the RVEDP between the RCA proximal and LCA groups. Thus, RA dysfunction in the RCA proximal group appeared to be due to myocardial damage rather than to afterload mismatch. These findings suggest that RA dysfunction may occur in patients with an inferior MI who have an obstructive lesion of the proximal RCA.

Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia.

We isolated a novel human ATP-binding cassette (ABC) transporter cDNA, determined its nucleotide sequence, and designated it human ABC7 (hABC7). The nucleotide sequence was highly homologous to the ATM1 gene in yeast, which encodes an ABC transporter (yAtm1p) located in the mitochondrial inner membrane. The deduced human product, a putative half-type transporter, consists of 752 amino acids that are 48.9% identical to those of yAtm1p. A computer-assisted protein structural and localization analysis revealed that the mitochondrial targeting signal of yAtm1p is conserved in the N-terminal region of the primary sequence of the hABC7 protein, and therefore this product is also likely to be located in the mitochondrial inner membrane. The evidence strongly suggests that the hABC7 gene is a counterpart of ATM1 and that its product is probably involved in heme transport. We mapped the hABC7 gene to chromosome Xq13.1-q13.3 by fluorescence in-situ hybridization. As band Xq13 has been implicated in X-linked sideroblastic anemia with spinocerebellar ataxia, hABC7 becomes a candidate gene for this heritable disorder.

[Evaluation of cardiac function by various cardiac imaging techniques in mitochondrial cardiomyopathy: a case report].

A 39-year-old man with cardiomyopathy due to point mutation of mitochondrial DNA(3243) was admitted to our hospital because of exertional dyspnea accompanied by hearing disturbance and diabetes mellitus. Echocardiography revealed asymmetric hypertrophy of the anterolateral and posterior walls and systolic dysfunction of the left ventricle (fractional shortening = 18%). Pulsed Doppler mitral inflow velocity wave showed a pseudonormalized pattern. Iodine-123 betamethyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP) myocardial scintigraphy showed decreased accumulation in the anterolateral, posterior, and apical walls. Left ventriculography showed moderately decreased ejection fraction (43%), and left ventricular end-diastolic pressure was mildly elevated (18 mmHg). Angiography showed normal coronary arteries, but coronary flow reserve measured by administering intravenous adenosine triphosphate was impaired in the left anterior descending and left circumflex arteries compared to the right coronary artery. Intracellular accumulations of abnormal mitochondria were detected by histologic examination of the cardiac and skeletal muscles. Evaluation of cardiac function showed that the area of myocardial hypertrophy was nearly consistent with the region of decrease in 123I-BMIPP accumulation and coronary flow reserve.

Isolation and expression of a cDNA for human brain fatty acid-binding protein (B-FABP).

We have isolated and sequenced a novel 754-bp human fetal brain cDNA encoding a fatty acid-binding protein (FABP). The cDNA contains an open reading frame of 396 nucleotides (132 amino acids). Northern analysis revealed small amounts of a 1.2-kb transcript in adult human brain and a shorter transcript in skeletal muscle, but no message was detected in other tissues examined. On the other hand, it was abundantly expressed in fetal brain but not in fetal lung, liver or kidney tissues. The elevated level of transcript at immature stages and its subsequent decline In adult brain indicate that the encoded protein may be essential for development of the human brain.

Tricuspid inflow and regurgitant flow dynamics after mitral valve replacement: differences relating to surgical repair of the tricuspid valve.

BACKGROUND AND AIMS OF THE STUDY: Changes in tricuspid inflow and regurgitant flow dynamics were evaluated in patients with functional tricuspid regurgitation (TR) who underwent mitral valve replacement (MVR) with and without tricuspid annuloplasty (TAP). METHODS: In a group of 30 patients, all with atrial fibrillation, 15 underwent TAP performed according to the modified De Vega technique; the remaining 15 did not undergo TAP. Patients were studied before and serially after surgery, using pulsed and color Doppler echocardiography. The mean follow up was 4.7 years in the TAP group and 5.1 years in the non-TAP group. RESULTS: In the TAP group, immediately after surgery, the area of the TR jet decreased markedly, and the deceleration time of the tricuspid inflow velocity wave was significantly prolonged compared with that before surgery. By contrast, in the non-TAP group, both the area of the TR jet and deceleration time of tricuspid inflow velocity were virtually unchanged. The area of the TR jet remained small for a long period in the TAP group, but in non-TAP patients was increased in four cases over seven years, with two patients developing right-sided heart failure. Recent data showed the area of the TR jet to be significantly smaller, with maximum tricuspid inflow velocity significantly increased, and deceleration time of the tricuspid inflow velocity wave significantly prolonged in the TAP group compared with the non-TAP group. CONCLUSIONS: In patients with functional tricuspid regurgitation undergoing MVR, concomitant TAP may cause mild tricuspid stenosis, but produces sustained preventive effects against TR. Careful follow up is needed in patients who have not undergone TAP, as TR is not markedly decreased and may even be exacerbated. Aggressive TAP is recommended in patients showing dilatation of the tricuspid annulus, even if TR is mild.

Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1.

Hypoglycemia is among the most injurious metabolic disorders caused by endotoxemia. In experimental endotoxemia with lipopolysaccharide (LPS) in animals, a marked glucose consumption is observed in macrophage-rich organs. However, the direct effect of LPS on the uptake of glucose by macrophages has not been fully understood, and the present study was undertaken to shed light on this point. The consumption and uptake of glucose, as measured with 2-deoxy-D-[3H]glucose, by murine peritoneal exudate macrophages in culture were accelerated two- to threefold by stimulation with 3 ng of LPS per ml. The rate of glucose uptake reached a plateau after 20 min of stimulation and remained at the maximum as long as LPS was present. Northern (RNA) blot analysis with cDNA probes for five known isoforms of glucose transporter (GLUT) revealed that the expression of GLUT by macrophages was restricted to the GLUT1 isoform during LPS stimulation and the amount of GLUT1 mRNA was increased by the stimulation. These results suggest that macrophage responses to LPS are supported by a rapid and sustained glucose influx via GLUT1 and that this is a participating factor in the development of systemic hypoglycemia when endotoxemia is prolonged.

Molecular cloning of a novel human cDNA, RT14, containing a putative ORF highly conserved between human, fruit fly, and nematode.

From a human fetal-brain cDNA library we isolated a novel gene, designated RT14, whose cDNA contained an open reading frame of 375 nucleotides encoding 125 amino acids. A 71-amino-acids region of the predicted peptide sequence showed 62% identity with a putative peptide encoded in the region close to Drosophila Tra-2. It also showed significant homology with the putative peptide of T20G5.10 of C. elegans. Northern-blot analysis revealed expression of 0.7-kb and 1.1-kb transcripts in all human tissues examined.

Hampered expression of isoaspartyl protein carboxyl methyltransferase gene in the human cataractous lens.

Isoaspartyl protein carboxyl methyltransferase (PIMT) is implicated in the repair of age-damaged proteins by converting altered aspartic acid residues to normal L-aspartic acid residues. Northern blot and reverse transcription (RT)-PCR analyses have revealed that PIMT gene expression in the human lens is detected exclusively in epithelial cells, and that the mRNA levels in cataractous lens epithelia are significantly lower than those in normal age-matched lens tissue. These results suggest that PIMT may play a vital role in maintaining the clarity of the lens and preventing cataract formation.