Photorefractive keratectomy: measuring the matrix metalloproteinase activity and chondroitin sulfate concentration in tear fluid

We herein report the case of a 20-year-old man who underwent a photorefractive keratectomy (PRK). We measured matrix metalloproteinase-9 (MMP-9) activity and chondroitin 4 sulfate and chondroitin 6 sulfate concentrations in tear fluid. Tear fluid was collected pre-operatively via microcapillary tube, and was collected postoperatively on the first and fourth days, and after one week, one month, three months, and six months. Samples were formulated by dilution with 200 μL of saline. MMP-9 activity was analyzed by an enzyme immunocapture activity assay, and the concentrations of chondroitin sulfate were analyzed by enzyme-linked immunosorbent assay. No complications were observed after surgery, except for a minimal subepithelial haze. Although MMP-9 activity changed on the fourth postoperative day, the activity changed only minimally at this time. Chondroitin 4 sulfate concentrations in tear fluid increased dramatically from one week to one month, decreased transiently at three months, and increased by six months. The chondroitin 6 sulfate concentration did not normalize within one week, and decreased from one week to three months compared with the preoperative score, and was close to the preoperative score at six months. We conclude that corneal wound healing was still incomplete six months after PRK, and chondroitin 4 sulfate appears to be critical in this process

Cognitive Profile of Idiopathic Normal Pressure Hydrocephalus

Background/Aims: Frontal lobe dysfunction is believed to be a primary cognitive symptom in idiopathic normal pressure hydrocephalus (iNPH); however, the neuropsychology of this disorder remains to be fully investigated. The objective of this study was to delineate a comprehensive profile of cognitive dysfunction in iNPH and evaluate the effects of cerebrospinal fluid (CSF) shunt surgery on cognitive dysfunction. Methods: A total of 32 iNPH patients underwent neuropsychological testing of memory, attention, language, executive function, and visuoperceptual and visuospatial abilities. Of these 32 patients, 26 were reevaluated approximately 1 year following CSF shunt surgery. The same battery of tests was performed on 32 patients with Alzheimer’s disease (AD) and 30 healthy elderly controls. Results: The iNPH patients displayed baseline deficits in attention, executive function, memory, and visuoperceptual and visuospatial functions. Impairments of attention, executive function, and visuoperceptual and visuospatial abilities in iNPH patients were more severe than in those with AD, whereas the degree of memory impairment was comparable to that in AD patients. A significant improvement in executive function was observed following shunt surgery. Conclusion: Patients with iNPH are impaired in various aspects of cognition involving both ‘frontal’ executive functions and ‘posterior cortical’ functions. Shunt treatment can ameliorate executive dysfunction

Nuclear translocation of ATBF1 is a potential prognostic maker for skin cancer

The AT motif binding factor 1 (ATBF1) is expressed in varioustissues, such as brain, liver, lung, and gastrointestinal tract, and hasan important role in cell differentiation in organs. ATBF1 interacts withPIAS3, a protein inhibitor for activated signal transducer and activatorof transcription (STAT3), to suppress STAT3 signaling, which has criticalroles in cell proliferation, migration, and survival. We hypothesized thatATBF1 is a useful prognostic marker for skin cancer. We performed immunohistochemicalanalyses of squamous cell carcinoma (SCC, n=7),basal cell carcinoma (BCC, n=4), and Bowen’s disease (n=4) tissues usingan anti-ATBF1 monoclonal antibody. All cases of BCC and Bowen’sdisease exhibited intense nuclear ATBF1 staining, whereas only someSCC cases exhibited weakly positive nuclear ATBF1 staining. SCC andBowen’s disease showed intense nuclear STAT3 staining, while BCC hadfew STAT3-positive nuclei. Based on these observations, nuclear ATBF1staining was associated with low malignancy profiles. The pattern ofATBF1 staining is a potential prognostic marker for skin cancer

Efficacy of Brigatinib in Patients With Advanced ALK-Positive NSCLC Who Progressed on Alectinib or Ceritinib: ALK in Lung Cancer Trial of brigAtinib-2 (ALTA-2)

Circulating tumor DNA; Non–small cell lung cancer; Tumor biomarkerADN tumoral circulante; Cáncer de pulmón de células no pequeñas; Biomarcador tumoralADN tumoral circulant; Càncer de pulmó de cèl·lules no petites; Biomarcador tumoralIntroduction Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors. Methods In this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed. Results Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5–17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0–35.8), median duration of response, 6.3 months (95% CI: 5.6–not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5–5.8). mPFS was 1.9 months (95% CI: 1.8–3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8–39.9); mPFS was 3.8 months (95% CI: 1.9–5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%. Conclusions In ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion

Fetal Goitrous Hypothyroidism due to Maternal Thyroid Stimulation-Blocking Antibody: A Case Report

Most fetal goitrous hypothyroidisms are reportedly caused by the maternal use of an antithyroid drug or fetal dyshormonogenesis. However, fetal goitrous hypothyroidism due to the transplacental passage of maternal thyroid stimulation-blocking antibody (TSBAb) is extremely rare. A woman at 28 weeks of gestation was found to have a fetal goiter by ultrasonography. Because the maternal serum showed hypothyroidism with an elevated titer of TSBAb, levothyroxine sodium was administered. The patient delivered a male infant, 3,412 g, with a goiter at term. Umbilical blood revealed primary hypothyroidism with increased TSBAb, and the infant was given levothyroxine sodium. After a month, neonatal thyroid function and TSBAb levels became normal. Attention should be paid to possible fetal hypothyroidism when a fetal goiter is observed to avoid impaired mental development of the neonate.ArticleFETAL DIAGNOSIS AND THERAPY. 28(4):220-224 (2010)journal articl

Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva

酸化的リン酸化の抑制がFOPの新たな治療法に繋がる可能性. 京都大学プレスリリース. 2024-03-11.Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated ACVR1/mTORC1 cascade induces HO in progenitors in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA-sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A–induced chondrogenesis of mesenchymal stem cells derived from FOP patient–specific induced pluripotent stem cells. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, along with increased mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, whereas OXPHOS inhibitor IACS-010759 inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury–induced enrichment of fibro/adipogenic progenitor genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target