Early Detection and Treatment of Congenital Cataracts Using Fetal Ultrasound: A Case of a Newborn With a Family History of Congenital Cataracts.

This case study highlights the advances in fetal ultrasonography, illustrating its role in early detection and management of congenital cataracts. We present the case of a male infant with a family history of congenital cataracts, where an in-utero ultrasound examination at 25 weeks of gestation revealed potential cataracts. His mother and brother underwent cataract surgery. After birth examination revealed that the infant was diagnosed with bilateral congenital cataracts at two days. Bilateral lens aspiration and anterior vitrectomy without intraocular lens insertion were done. Postnatal examinations and surgical interventions, including bilateral lens phacoemulsification and anterior vitrectomy without intraocular lens insertion, were conducted. This study discusses the importance of early detection, especially in familial cases, and the role of prenatal and postnatal care in managing congenital cataracts. It underscores the need for collaboration between ophthalmologists and obstetricians and the value of psychological support for the parents. The findings advocate for proactive fetal monitoring, particularly in genetically predisposed cases, to facilitate early diagnosis and treatment planning.

[A Case of Rectosigmoid T1b Cancer Which Had Been Under Control by Combination of Loco-Regional Therapies].

According to the Japanese Colorectal ESD/EMR guidelines, radical surgery should be recommended for additional treatment of T1 colorectal cancer(CRC)if pathological findings of the lesion after endoscopic resection show unfavorable factors to be evaluated as curative resection, considering the probability of lymph node metastasis and general condition of patients. We report a case of a 74-year-old man with T1b rectosigmoid(RS)cancer, whose pulmonary metastasis(PM) was curatively resected during the postoperative period of ESD for primary lesions. The patient underwent ESD in November 2018 for Type 0-Isp CRC in the RS junction, revealed using colonoscopy, which was performed for the examination of blood stool in September 2018. The patient had suffered from pulmonary tuberculosis in his thirties and regularly visited our hospital for COPD. He was under close observation after ESD because the depth of the lesion, which was pathologically diagnosed as T1b, was the only factor evaluated as non-curative. In April 2020, chest CT and FDG-PET/CT findings revealed the occurrence of PM. Subsequently, video-assisted wedge resection of the lung was performed for the treatment of PM, which was pathologically confirmed with a size of 10 mm. The patient has survived relapse-free to date, for 30 months after the resection of the primary lesion.

[Relapse-Free Survival of over 54 Months after ESD Resection in an Elderly Patient Considered to Have Non-Curative Early Gastric Cancer].

According to the Japanese Gastric Cancer Treatment Guideline(GL), radical surgery is recommended as an additional treatment for early gastric cancer(EGC)patients with endoscopic submucosal dissection(ESD)evaluated as non-curative for fear of lymph node metastasis(LNM). However, the reported probability of LNM was approximately 10%. Therefore, the recommendation might be aggressive for elderly patients or those in poor physical conditions. Under this context, surveillance post non-curative ESD has emerged as an acceptable option. We reported a case of an elderly patient who survived EGC for over 54 months as relapse-free with ESD resection evaluated as non-curative. An 84-year-old woman underwent ESD in July 2014 for EGC, which was deemed as non-curative with negative surgical margins. The patient had pre-existing severe bronchial asthma. Given the age and the comorbidities, the patient preferred close surveillance to radical surgery. After 54 months of surveillance, no recurrence of the initial EGC was found. However, during the annual check-ups, 2 metachronous cancers were found in July 2016 and June 2018 respectively. Both metachronous cancers were curatively resected with ESD.

[A Case of Advanced Gastric Cancer Who Peritoneal Dissemination but Survived over 40 Months with Locoregional Therapies].

Several recent case reports have demonstrated long survival cases of advanced gastric cancer(AGC)patients suffering from peritoneal dissemination(PD)treatedwith effective chemotherapy; however, these AGC patients have poor prognosis in general. We report a case of AGC who hadsurvivedPD over 40 months with locoregional therapies. A 58-year-oldmale underwent distal gastrectomy for AGC with localized PD. Although we recommended postoperative chemotherapy, he chose surveillance as his will. Eighteen months postoperatively, CT scan revealedrecurrence of PD, andPET -CT showedonly one site of recurrent nodule. The patient chose locoregional therapy, ie, resection of the recurrent nodule instead of chemotherapy. Pathological exam confirmedthe recurrence of AGC, andabd ominal lavage cytology was classifiedas V. Even after these pathological findings, the patient refused to receive chemotherapy. At 39 months postoperatively, he developed subileus due to multiple recurrence of PD. At 40 months postoperatively, we performedchemotherapy because locoregional therapy was not supposedto be appropriate for these multiple lesions. However, the patient movedto another hospital after 1 course of chemotherapy because of his continuedrefusal to receive chemotherapy.

[A Case of Obstructive Jaundice Caused by Recurrent Gastric Cancer Previously Treated with Distal Gastrectomy and Roux-en-Y Reconstruction Whose Obstruction Was Relieved by ERCP for Altered Gastrointestinal Anatomy Using Conventional Endoscopes].

There have been many reports on ERCP for patients with alteredgastrointestinal anatomy(AGA), using balloon-assisted enteroscopy(BAE); however, BAE is not commonly usedin practice because it requires special endoscopic systems and accessories, which are time-consuming to operate. For this reason, patients with AGA who suffer from obstructive jaundice (OJ)might receive PTBD in general practice during emergency situations. We report a case of OJ, caused by recurrent gastric cancer andpreviously treatedwith distal gastrectomy andRoux -en-Y reconstruction(DGRY). The obstruction was relieved by ERCP for AGA, using conventional endoscopes. A 74-year-oldwoman, who hadpreviously undergone DGRY for advanced gastric cancer(AGC)andhadbeen receiving first-line chemotherapy for AGC recurrence, was admitted to our hospital for treatment of OJ, causedby progression of recurrent AGC, in July 2016. ERCP for AGA was performedusing conventional endoscopes, andOJ was successfully relievedby the insertion of a self-expandable metallic stent. Subsequently, second-line chemotherapy was administeredandthe patient enteredPR after 2 courses of chemotherapy.

[A Case of Malignant Colonic Obstruction Bearing Another Synchronous Obstructive Lesion in the Anal Side of the Colon].

There are several reasons for failure in the insertion of a self-expandable metallic stent(SEMS)into a malignant colonic obstruction(MCO)including difficulty in insertion of the catheter or guidewire through the stenotic lumen into the oral side or perforation relatedto the technique. Herein, we report a case of MCO bearing another synchronous obstructive lesion in the anal side of the colon that couldhave explainedthe difficulty in the insertion of the SEMS into the stenosis locatedin the oral side, which might have indicated the need for an emergency operation for relieving the obstruction. A 76-year-oldman with epigastralgia andmelena was admittedto our hospital andhe was diagnosedwith a MCO in the ascending colon. A series of examinations performedafter admission revealedthat the patient hadanother synchronous obstructive lesion in the descending colon, which made colonoscope insertion at the oral side difficult. The next day after admission, we observed that fasting relievedthe patient from abdominal pain causedby obstruction; therefore, we performedSEMS insertion into the MCO of the descending colon followed by SEMS insertion into the ascending colon after 6 days. These serial SEMS insertions facilitated the oral administration of the diet and the patient was discharged 15 days after admission. The patient was readmittedto our hospital andhe underwent a radical operation for both lesions in June 2015.

[Pulmonary metastasis of sarcomatous component of adrenocortical carcinoma].

A 43-year-old man presented with a pulmonary nodule in the left lower lobe and he consulted our hospital one year after resection of left adrenocortical carcinoma. We performed a wedge resection of the left lower pulmonary lobe for diagnosis. The tumor was diagnosed as a metastatic sarcoma, but the primary site could not be resolved. We assessed the histopathology of the adrenal tumor, which was obtained from the patient's former hospital, and it showed that the tumor consisted of both carcinomatous and sarcomatous components. This enabled us to diagnose the nodule as a pulmonary metastasis from the adrenocortical carcinoma. Adrenocortical carcinoma with a sarcomatous component is very rare. This case is a first report of a resected pulmonary metastasis of sarcomatous component of adrenocortical carcinoma.

[Fibrosing mediastinitis diagnosed by thoracoscopic biopsy].

We report a rare case of fibrosing mediastinitis diagnosed by thoracoscopic biopsy. A 56-year-old female visited our hospital with an abnormal mediastinal shadow on chest X ray. Chest computed tomography revealed a paravertebral tumor from Th9 to Th11. Pathological examination of thoracoscopic biopsy specimen showed fibrous tissue with mild inflammation and no malignant feature. Final diagnosis was idiopathic fibrosing mediastinitis. The paravertebral lesion shrinked spontaneously 5 months later after biopsy.

Eukaryote-specific insertion elements control human ARGONAUTE slicer activity.

We have solved the crystal structure of human ARGONAUTE1 (hAGO1) bound to endogenous 5'-phosphorylated guide RNAs. To identify changes that evolutionarily rendered hAGO1 inactive, we compared our structure with guide-RNA-containing and cleavage-active hAGO2. Aside from mutation of a catalytic tetrad residue, proline residues at positions 670 and 675 in hAGO1 introduce a kink in the cS7 loop, forming a convex surface within the hAGO1 nucleic-acid-binding channel near the inactive catalytic site. We predicted that even upon restoration of the catalytic tetrad, hAGO1-cS7 sterically hinders the placement of a fully paired guide-target RNA duplex into the endonuclease active site. Consistent with this hypothesis, reconstitution of the catalytic tetrad with R805H led to low-level hAGO1 cleavage activity, whereas combining R805H with cS7 substitutions P670S and P675Q substantially augmented hAGO1 activity. Evolutionary amino acid changes to hAGO1 were readily reversible, suggesting that loading of guide RNA and pairing of seed-based miRNA and target RNA constrain its sequence drift.

The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome.

The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1--a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing--contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.

Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation.

DNMT1, the major maintenance DNA methyltransferase in animals, helps to regulate gene expression, genome imprinting, and X-chromosome inactivation. We report on the crystal structure of a productive covalent mouse DNMT1(731-1602)-DNA complex containing a central hemimethylated CpG site. The methyl group of methylcytosine is positioned within a shallow hydrophobic concave surface, whereas the cytosine on the target strand is looped out and covalently anchored within the catalytic pocket. The DNA is distorted at the hemimethylated CpG step, with side chains from catalytic and recognition loops inserting through both grooves to fill an intercalation-type cavity associated with a dual base flip-out on partner strands. Structural and biochemical data establish how a combination of active and autoinhibitory mechanisms ensures the high fidelity of DNMT1-mediated maintenance DNA methylation.

Long-range pseudoknot interactions dictate the regulatory response in the tetrahydrofolate riboswitch.

Tetrahydrofolate (THF), a biologically active form of the vitamin folate (B(9)), is an essential cofactor in one-carbon transfer reactions. In bacteria, expression of folate-related genes is controlled by feedback modulation in response to specific binding of THF and related compounds to a riboswitch. Here, we present the X-ray structures of the THF-sensing domain from the Eubacterium siraeum riboswitch in the ligand-bound and unbound states. The structure reveals an "inverted" three-way junctional architecture, most unusual for riboswitches, with the junction located far from the regulatory helix P1 and not directly participating in helix P1 formation. Instead, the three-way junction, stabilized by binding to the ligand, aligns the riboswitch stems for long-range tertiary pseudoknot interactions that contribute to the organization of helix P1 and therefore stipulate the regulatory response of the riboswitch. The pterin moiety of the ligand docks in a semiopen pocket adjacent to the junction, where it forms specific hydrogen bonds with two moderately conserved pyrimidines. The aminobenzoate moiety stacks on a guanine base, whereas the glutamate moiety does not appear to make strong interactions with the RNA. In contrast to other riboswitches, these findings demonstrate that the THF riboswitch uses a limited number of available determinants for ligand recognition. Given that modern antibiotics target folate metabolism, the THF riboswitch structure provides insights on mechanistic aspects of riboswitch function and may help in manipulating THF levels in pathogenic bacteria.

WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity.

DNA double-stranded breaks present a serious challenge for eukaryotic cells. The inability to repair breaks leads to genomic instability, carcinogenesis and cell death. During the double-strand break response, mammalian chromatin undergoes reorganization demarcated by H2A.X Ser 139 phosphorylation (gamma-H2A.X). However, the regulation of gamma-H2A.X phosphorylation and its precise role in chromatin remodelling during the repair process remain unclear. Here we report a new regulatory mechanism mediated by WSTF (Williams-Beuren syndrome transcription factor, also known as BAZ1B)-a component of the WICH complex (WSTF-ISWI ATP-dependent chromatin-remodelling complex). We show that WSTF has intrinsic tyrosine kinase activity by means of a domain that shares no sequence homology to any known kinase fold. We show that WSTF phosphorylates Tyr 142 of H2A.X, and that WSTF activity has an important role in regulating several events that are critical for the DNA damage response. Our work demonstrates a new mechanism that regulates the DNA damage response and expands our knowledge of domains that contain intrinsic tyrosine kinase activity.