First-line treatment and overall survival in EGFR mutation-positive advanced non-small cell lung cancer: a national cohort study.

OBJECTIVE: Non-squamous non-small cell lung cancer (NSCLC) is the first leading cause of cancer-related deaths in Taiwan. This study aimed at evaluating the effectiveness of first-line targeted therapy for advanced epidermal growth factor receptor (EGFR) mutation-positive non-squamous NSCLC in Taiwan. PATIENTS AND METHODS: This was a real-world, retrospective, observational study of patients diagnosed with advanced non-squamous NSCLC (N=63,248). Between 2011 and 2019, 19,458 patients received targeted therapy and 22,994 patients received chemotherapy alone; between 2002 and 2010, 20,796 patients received chemotherapy alone. Overall survival (OS) was determined. RESULTS: The median OS for patients treated with first-line targeted therapy (22.9 months) was longer than that of patients receiving chemotherapy alone (11.7 months). HR: 0.521, log-rank test, p<0.001. CONCLUSIONS: These data represent the potential survival outcomes of Taiwanese patients with advanced EGFR mutation-positive non-squamous NSCLC in clinical practice.

Effects of direct-acting antiviral therapy for patients with advanced hepatocellular carcinoma and concomitant hepatitis C-A population-based cohort study.

OBJECTIVE: We analyzed real-world data to elucidate the effects of anti-Hepatitis C virus (HCV) direct-acting antiviral (DAA) therapy on survival in patients with advanced hepatocellular carcinoma (HCC) and concomitant HCV infection treated with sorafenib. MATERIALS AND METHODS: This population-based retrospective cohort study used the Taiwan National Health Insurance Research Database and the Registration System for Patients Treated with Oral Hepatitis C Antivirals to identify patients with advanced HCC and concomitant HCV infection who received initial targeted therapy (sorafenib) in 2018-2019. The overall survival (OS) of the DAA and non-DAA groups were compared using the Kaplan-Meier survival analysis. Propensity score matching was performed using a ratio of 1:4 to reduce confounding between the DAA and non-DAA groups. RESULTS: The study included 1,684 patients (122 DAA and 1,562 non-DAA users) with HCC and concomitant HCV infection who used sorafenib for the first time in 2018-2019. The Kaplan-Meier survival analysis indicated that advanced HCC patients who used DAAs had longer OS compared to non-DAA patients. The mean survival times were 20.7 months for DAA and 12.5 months for non-DAA. Results obtained after propensity matching indicated a significant difference in OS between the DAA and non-DAA groups. CONCLUSIONS: The analysis of big data from the Taiwan National Health Insurance Research Database revealed that advanced HCC patients on sorafenib benefited from DAAs as a treatment for HCV infection. Patients whose HCV infection was cured had better OS.

Real-world results of immune checkpoint inhibitors from the Taiwan National Health Insurance Registration System.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) are a major advance in cancer treatment, but their payment benefits are unclear, resulting in financial risk. In Taiwan, the National Health Insurance Administration (NHIA) has adapted risk-sharing mechanisms to cover ICIs by collecting and assessing real-world evidence, such as case registration data, to adjust benefit packages for each medication, increase payment benefits of ICIs, and enable national health insurance sustainability. PATIENTS AND METHODS: This nationwide, multicenter, retrospective cohort study assessed the real-world use, effectiveness, and safety of ICIs reimbursed by the NHIA for treating multiple advanced cancers in Taiwan. We obtained data mainly from the NHIA Immune Checkpoint Inhibitor Registry Database. RESULTS: Between April 1, 2019, and March 31, 2020, 1644 patients received at least one dose of ICIs. The overall response rate (RR) was 29.1%. The metastatic urothelial carcinoma of patients ineligible for chemotherapy showed the highest RR. The estimated median progression-free survival (PFS) was 2.8 months (95% confidence interval [CI]=2.7-3 months), and renal cell carcinoma showed the longest PFS. The median PFS was reached in patients with most cancers except classic Hodgkin's lymphoma, which had a small sample size. The estimated survival probability was 50%. CONCLUSIONS: Under the national registration tracking system, Taiwan's high-cost drug policy has enabled access to new medicines and maximized patient benefits.

Genetic diversity analysis of okra (Abelmoschus esculentus L.) by inter-simple sequence repeat (ISSR) markers.

Okra (Abelmoschus esculentus L.) is not only a nutrient-rich vegetable but also an important medicinal herb. Inter-simple sequence repeat (ISSR) markers were employed to investigate the genetic diversity and differentiation of 24 okra genotypes. In this study, the PCR products were separated by electrophoresis on 8% nondenaturing polyacrylamide gel and visualized by silver staining. The 22 ISSR primers produced 289 amplified DNA fragments, and 145 (50%) fragments were polymorphic. The 289 markers were used to construct the dendrogram based on the unweighted pair-group method with arithmetic average (UPGMA) cluster analysis. The dendrogram indicated that 24 okras were clustered into 4 geographically distinct groups. The average polymorphism information content (PIC) was 0.531929, which showed that the majority of primers were informative. The high values of allele frequency, genetic diversity, and heterozygosity showed that primer-sample combinations produced measurable fragments. The mean distances ranged from 0.045455 to 0.454545. The dendrogram indicated that the ISSR markers succeeded in distinguishing most of the 24 varieties in relation to their genetic backgrounds and geographical origins.

Long-term disease-free survival in three ovarian cancer patients with a single relapse.

Recurrent ovarian cancer with long-term survival is uncommon and often associated with poor prognosis. We report three cases of patients with advanced ovarian cancer who have achieved long-term disease-free survival following a single prior relapse. Case 1 relapsed with a localized bulky tumor and received a complete surgical resection and chemotherapy. Case 2 had a persistent central pelvic tumor after debulking surgery and second-line chemotherapy, and yet achieved excellent control with concurrent chemoradiation to the true pelvis. Case 3 relapsed with paraaortic lymph node metastasis and probable lung metastasis (subsequently negated by positron emission tomography) and received chemotherapy alone. These three patients have since remained disease-free for 13, 12, and seven years, respectively, since their first relapse. We conclude that select patients can obtain long-term disease-free survival after the first relapse by accurate restaging and aggressive multimodality treatment.

Successful salvage treatment of recurrent endometrial cancer with multiple lung and abdominal metastases.

The prognosis of recurrent endometrial carcinoma is generally poor except for isolated vaginal or pelvic relapse without previous radiation. Recurrences associated with infield failure or distant metastasis carry a poor prognosis. We report a case of recurrent endometrial carcinoma treated with cytoreductive surgery, targeted radiation to lung metastasis defined by CT and PET and adjuvant chemo-hormone therapy followed by maintenance progestin therapy with a good outcome. This case implied that chemo-hormone therapy with targeted radiation should be evaluated in recurrent endometrial cancer with positive progesterone receptor for salvage treatment.

Suppression of inflammation-associated factors by indole-3-carbinol in mice fed high-fat diets and in isolated, co-cultured macrophages and adipocytes.

AIMS: This study investigated the effects of indole-3-carbinol (I3C), a compound from cruciferous vegetables, on various parameters related to obesity, in particular, the parameters of infiltration by macrophages and of inflammatory cytokines expressed during the co-culture of adipocytes and macrophages. METHODS: Male C57BL/6 mice were fed with a control diet (C group), high-fat diet (HF group) and HF+5 mg kg(-1) I3C (HFI group). The I3C was intraperitoneally injected (HFI group) for 12 weeks. Epididymal adipose tissue (AT) was collected and stained for F4/80, a marker of macrophages. RESULTS: The immunohistochemical staining for F4/80 indicated a greater presence of macrophages in the HF group than in AT from the control and HFI groups. Furthermore, I3C treatment, in an in vitro cell culture system, decreased expression of inducible nitric oxide synthase (iNOS), decreased nitrite content and enhanced expression of peroxisome proliferator-activated receptor (PPAR-γ). Moreover, in vitro cell culture studies revealed that I3C inhibited intracellular lipid accumulation in hypertrophied adipocytes. In macrophage and primary adipocyte co-culture, I3C inhibited expression of interleukin-6 (IL-6). CONCLUSIONS: In vivo treatment with I3C reduced the infiltration of macrophages in AT, and in vitro addition of I3C to co-cultured macrophages and adipocytes reduced nitrite production and IL-6 expression. With cultures of adipocytes only, I3C inhibited accumulation of intracellular lipid, either by disrupting differentiation, or by directly inhibiting triglyceride synthesis.

A major QTL on chromosome 11 influences psychostimulant and opioid sensitivity in mice.

The identification of genes influencing sensitivity to stimulants and opioids is important for determining their mechanism of action and may provide fundamental insights into the genetics of drug abuse. We used a panel of C57BL/6J (B6; recipient)x A/J (donor) chromosome substitution strains (CSSs) to identify quantitative trait loci (QTL) for both open field activity and sensitivity to the locomotor stimulant response to methamphetamine (MA). Mice were injected with saline (days 1 and 2) and MA (day 3; 2 mg/kg i.p.). We analyzed the total distance traveled in the open field for 30 min following each injection. CSS-8, -11 and -16 showed reduced MA-induced locomotor activity relative to B6, whereas CSS-10 and -12 showed increased MA-induced locomotor activity. Further analysis focused on CSS-11 because it was robustly different from B6 following MA injection, but did not differ in activity following saline injection and because it also showed reduced locomotor activity in response to the mu-opioid receptor agonist fentanyl (0.2 mg/kg i.p.). Thus, CSS-11 captures QTLs for the response to both psychostimulants and opioids. Using a B6 x CSS-11 F(2) intercross, we identified a dominant QTL for the MA response on chromosome 11. We used haplotype association mapping of cis expression QTLs and bioinformatic resources to parse among genes within the 95% confidence interval of the chromosome 11 QTL. Identification of the genes underlying QTLs for response to psychostimulants and opioids may provide insights about genetic factors that modulate sensitivity to drugs of abuse.

Quadruple-bend achromatic low emittance lattice studies.

A quadruple-bend achromatic (QBA) cell, defined as a supercell made of two double-bend cells with different outer and inner dipole bend angles, is found to provide a factor of 2 in lowering the beam emittance relative to the more conventional double-bend achromat. The ratio of bending angles of the inner dipoles to that of the outer dipoles is numerically found to be about 1.5-1.6 for an optimal low beam emittance in the isomagnetic condition. The QBA lattice provides an advantage over the double-bend achromat or the double-bend nonachromat in performance by providing a small natural beam emittance and some zero-dispersion straight sections. A lattice with 12 QBA cells and a preliminary dynamic aperture study serves as an example.

Craniofacial morphometric analysis of mandibular prognathism.

The purpose of this study was to provide more information about the morphological characteristics of the craniofacial complex in mandibular prognathism. Forty young adult males having mandibular prognathism were compared with 40 having normal occlusion. This was conducted to carry out geometric morphometric assessments to localize alterations, using Procrustes analysis and thin-plate spline analysis, in addition to conventional cephalometric techniques. Procrustes analysis indicated that the mean craniofacial, midfacial and mandibular morphology was significantly different in prognathic subjects compared with normal controls. This finding was corroborated by the multivariate Hotelling T(2)-test of cephalometric variables. Mandibular prognathism demonstrated a shorter and slightly retropositioned maxilla, a greater total length and anterior positioning of the mandible. Thin-plate spline analysis revealed a developmental diminution of the palatomaxillary region anteroposteriorly and a developmental elongation of the mandible anteroposteriorly, leading to the appearance of a prognathic mandibular profile. In conclusion, thin-plate spline analysis seems to provide a valuable supplement for conventional cephalometric analysis because the complex patterns of craniofacial shape change are visualized suggestive by means of grid deformations.

Geometric morphometric assessment of treatment effects of maxillary protraction combined with chin cup appliance on the maxillofacial complex.

The aim of this study was to investigate the treatment effects on the maxillofacial complex by maxillary protraction combined with chin cup therapy among growing children. An effective geometric morphometric assessment of cephalometric radiographs, using Procrustes analysis and thin-plate spline analysis, was applied to evaluate shape change in the craniofacial and midfacial configurations of a treated sample of 20 children with skeletal Class III malocclusion. This was compared with matched untreated skeletal Class III controls. Marked treatment induced change involved the maxilla and the mandible. Major deformation consisted of forward advancement of the maxillary complex with negligible rotation of the palatal plane and a forward direction of growth of the mandibular condyle associated with a restriction in sagittal advancement of the chin. Considerable dentoalveolar components contributed to the correction of anterior crossbite. Further detailed study of skeletofacial remodelling in response to maxillary protraction in other skeletal components, including the cranial base and the mandibular complex that contribute to Class III skeletal discrepancies, is warranted.

Midfacial and mandibular morphometry of children with Class II and Class III malocclusions.

There is insufficient evidence in conventional cephalometric analysis of the actual sites of putative maxillofacial change in Class II and Class III malocclusions. The purpose of this study was to provide more information about the morphological characteristics of the midfacial complex and mandible in children with Class II or III malocclusions. Seventy children with Class II, division 1 malocclusion and 70 children with Class III malocclusion were compared with 70 children with normal occlusion. This study was conducted to carry out geometric morphometric assessments to localize alterations using Procrustes analysis and thin-plate spline analysis. Procrustes analysis indicated the midfacial and mandibular morphologies differed between normal occlusion subjects and subjects with Class II or Class III malocclusion (P<0.0001). The deformations in subjects with Class II malocclusion may represent a developmental elongation of the palatomaxillary complex and a shortening of the mandible anteroposteriorly, which leads to the appearance of a protruding midface and retruding mandibular profile. In contrast, the deformations in subjects with Class III malocclusion may represent a developmental shortening of the palatomaxillary complex and elongation of the mandible anteroposteriorly, which leads to the appearance of a retrognathic midface and prognathic mandibular profile.

An enlarged sella turcica on cephalometric radiograph.

A 28-year-old male presented to the Orthodontic clinic for correction of his anterior crossbite due to mandibular prognathism as a result of pituitary adenoma with acromegaly. A radiographic cephalometric analysis and clinical orthodontic examination were made. This article describes in detail the methods of correcting the magnification of cephalometric linear measurements in sellar dimensions (length, depth and width) from lateral and posteroanterior cephalograms. Cephalometric findings revealed that the sella enlarged in all its dimensions with a deepening of the floor in this acromegalic case. We discuss the radiographic diagnosis of an enlarged sella turcica in intrasellar tumours and also emphasise the dentist's important role in the initial diagnosis of pituitary adenoma cases.

Thin-plate spline (TPS) graphical analysis of the mandible on cephalometric radiographs.

We describe two cases of Class III malocclusion with and without orthodontic treatment. A thin-plate spline (TPS) analysis of lateral cephalometric radiographs was used to visualize transformations of the mandible. The actual sites of mandibular skeletal change are not detectable with conventional cephalometric analysis. These case analyses indicate that specific patterns of mandibular transformation are associated with Class III malocclusion with or without orthopaedic therapy, and visualization of these deformations is feasible using TPS graphical analysis.

Correlation of cervical vertebra maturation with hand-wrist maturation in children.

The purpose of this study was to evaluate the reliability of cervical vertebra maturation as an indicator of skeletal age during the circumpubertal period. This was determined by correlating cervical vertebra maturation to hand-wrist maturation. The vertebral skeletal age was assessed using lateral cephalometric radiographs according to maturity indicators modified from Lamparski. The hand-wrist skeletal age was evaluated in radiographs with the system developed by Fishman. The sample consisted of 503 subjects (244 boys and 259 girls), aged 8 through 18 years. The Spearman rank correlation coefficients and Wilcoxon sign rank test showed that a statistically significant relationship existed between the two assessments. Both the intra- and inter-judge tests of reliability displayed no significant differences. The results of this study indicate that skeletal age assessment made from the maturational changes of cervical vertebrae were reliable, reproducible and valid.

Functional blocking of integrin-associated protein impairs memory retention and decreases glutamate release from the hippocampus.

We have previously demonstrated that integrin-associated protein is involved in memory consolidation of one-way inhibitory avoidance learning in rats and mice. In the present study, we examined the effects of functional blocking of integrin-associated protein on memory retention, long-term potentiation and glutamate release in mice as well as on cell attachment to extracellular matrix protein in primary cultures. The results indicated that integrin-associated protein monoclonal antibody miap301, when directly injected into the dentate gyrus of the hippocampus at moderate doses, significantly impairs memory retention in mice in the same one-way inhibitory avoidance task and decreases the amplitude of tetanic stimulation-induced long-term potentiation in dentate gyrus neurons. At a dose that effectively impairs both memory retention and long-term potentiation, integrin-associated protein monoclonal antibody also significantly blocks potassium chloride-induced glutamate release from the hippocampus in vivo. Results from western blot confirmed the presence of integrin-associated protein at the synaptic area. Cell adhesion experiments further revealed that integrin-associated protein monoclonal antibody markedly inhibits granular cell attachment to thrombospondin, the extracellular matrix protein known to bind integrin-associated protein, but not to collagen and laminin, the extracellular matrix proteins known to bind integrin. From these results we suggest that integrin-associated protein monoclonal antibody may impair synaptic plasticity and behavioral plasticity in mice through blockade of granular cell attachment to extracellular matrix protein and the subsequent signal transduction, and through inhibition of glutamate release from the hippocampus.

Characterization of the functional role of Asp141, Asp194, and Asp464 residues in the Mn2+-L-malate binding of pigeon liver malic enzyme.

Pigeon liver malic enzyme was inactivated and cleaved at Asp141, Asp194, and Asp464 by the Cu2+-ascorbate system in acidic environment. Site-specific mutagenesis was performed at these putative metal-binding sites. Three point mutants, D141N, D194N, and D464N; three double mutants, D(141,194)N, D(194,464)N, and D(141,464)N; and a triple mutant, D(141,194,464)N; as well as the wild-type malic enzyme (WT) were successfully cloned and expressed in Escherichia coli cells. All recombinant enzymes, except the triple mutant, were purified to apparent homogeneity by successive Q-Sepharose and adenosine-2',5'-bisphosphate-agarose columns. The mutants showed similar apparent Km,NADP values to that of the WT. The Km,Mal value was increased in the D141N and D194N mutants. The Km,Mn value, on the other hand, was increased only in the D141N mutant by 14-fold, corresponding to approximately 1.6 kcal/mol for the Asp141-Mn2+ binding energy. Substrate inhibition by L-malate was only observed in WT, D464N, and D(141,464)N. Initial velocity experiments were performed to derive the various kinetic parameters. The possible interactions between Asp141, Asp194, and Asp464 were analyzed by the double-mutation cycles and triple-mutation box. There are synergistic weakening interactions between Asp141 and Asp194 in the metal binding that impel the D(141,194)N double mutant to an overall specificity constant [k(cat)/(Kd,Mn Km,Mal Km,NADP)] at least four orders of magnitude smaller than the WT value. This difference corresponds to an increase of 6.38 kcal/mol energy barrier for the catalytic efficiency. Mutation at Asp464, on the other hand, has partial additivity on the mutations at Asp141 and Asp194. The overall specificity constants for the double mutants D(194,464)N and D(141,464)N or the triple mutant D(141,194,464)N were decreased by only 10- to 100-fold compared to the WT. These results strongly suggest the involvement of Asp141 in the Mn2+-L-malate binding for the pigeon liver malic enzyme. The Asp194 and Asp464, which may be oxidized by nonspecific binding of Cu2+, are involved in the Mn2+-L-malate binding or catalysis indirectly by modulating the binding affinity of Asp141 with the Mn2+.

Impaired memory retention and decreased long-term potentiation in integrin-associated protein-deficient mice.

Previously, we have demonstrated that integrin-associated protein (IAP) mRNA level is approximately fourfold higher in rats showing good retention performance (600 sec) than rats showing poor retention performance (< 80 sec) in an inhibitory avoidance learning paradigm. In the present study, we have used the gene-targeted IAP-deficient mice to further investigate the role of IAP involved in memory formation and hippocampal long-term potentiation (LTP) in vivo. Results revealed that there was a significant impairment in memory retention and a significant reduction in the magnitude of LTP in IAP-deficient mice when compared with the wild-type and heterozygote mice, whereas the wild-type and heterozygote animals did not show marked differences on these measures. Furthermore, the impairment in retention performance of IAP-deficient mice was not due to different sensitivities of these animals to the electric shock. When we examined locomotor activity and rotarod treadmill performance, no differences were observed among these three groups of animals either. Western blot analysis confirmed the lack of IAP protein in IAP-deficient mice, whereas IAP expression was similar in both the wild-type and heterozygote controls. These results together demonstrate that IAP plays an important role in the process of memory formation and synaptic plasticity in mice.

Ethnic dental analysis of shovel and Carabelli's traits in a Chinese population.

Chinese populations differ from Caucasoids by having a high prevalence of shovel trait and a low prevalence of Carabelli's trait. This study was conducted to investigate the association between the shovel and the Carabelli's traits in a Chinese population. The research design investigated a Chinese population that resides in southern Taiwan. The ancestors of this Chinese population migrated to Taiwan from mainland China, mainly from Fukien and Kwangtung. The effects of sex and age on Carabelli's trait were controlled in this investigation, as was the association between tooth size and Carabelli's trait. Results show that males were more likely to have Carabelli's trait expressed on teeth than females. The buccolingual diameter of Carabelli's trait teeth was larger than that of teeth without the trait. After controlling for sex, age, and tooth size, the existence of the shovel trait increased the likelihood of having Carabelli's trait by a factor of five and a half, which is a significant effect.

Craniofacial pattern of young adults with various types of malocclusion.

Craniofacial morphological characteristics of young adults with various malocclusions were investigated. Cephalometric radiographs of 100 Class I, 100 Class II, and 100 Class III cases were selected and subjected to counterpart analysis as described by Enlow. Results of individuals with normal occlusion revealed a mean value of 38.75 degrees for the angle of the middle cranial fossa relative to the posterior maxillary plane alignment (MCF/PM). This value was used as the basis for intrinsic alignment comparisons for all the other various parts. Classes I and II malocclusions were classified as either type A or B, depending on whether point A or B was protrusive in the functional occlusal plane (FOP). We found that type B was more common for Class I malocclusion. Further, these cases exhibited an underlying Class III character. We also noted that B groups had different structural craniofacial patterns relative to those seen in A groups. The difference between Class IA and Class IIA, or between Class IB and Class IIB was slight but quantitative. Class III and Class IIA individuals had distinctly different and essentially opposite underlying patterns. However, the composite compensatory result in Class IB case was, for the most part, effective.