Targeting the FGF/FGFR axis and its co-alteration allies.

BACKGROUND: We analyzed the FGF/FGFR and co-alteration cancer landscape, hypothesizing that combination therapy might be useful in the presence of co-drivers. MATERIALS AND METHODS: We describe FGF/FGFR-altered pathways, prognosis, and co-alterations [cBioPortal (N = 7574)] and therapeutic outcomes [University of California San Diego Molecular Tumor Board (MTB) (N = 16)]. RESULTS: Patients whose cancers harbored FGF/FGFR alterations (N = 1074) versus those without them (N = 6500) had shorter overall survival (OS) (median: 23.1 versus 26.4 months, P = 0.038) (cBioPortal). Only 6.1% (65/1074 patients) had no pathogenic co-alterations accompanying FGF/FGFR axis abnormalities. The most frequently co-altered pathways/genes involved: TP53 (70%); cell cycle (58%); PI3K (55%); and receptor tyrosine kinases and mitogen-activated protein kinase (MAPK) (65%). Harboring alterations in both FGF/FGFR and in the TP53 pathway or in the cell cycle pathway correlated with shorter OS (versus FGF/FGFR-altered without those co-altered signals) (P = 0.0001 and 0.0065). Four of 16 fibroblast growth factor receptor (FGFR) inhibitor-treated patients presented at MTB attained durable partial responses (PRs) (9, 12, 22+, and 52+ months); an additional two, stable disease (SD) of ≥6 months (13+ and 15 months) [clinical benefit rate (SD ≥ 6 months/PR) = 38%]. Importantly, six patients with cyclin pathway co-alterations received the CDK4/6 inhibitor palbociclib (75 mg p.o. 3 weeks on, 1 week off) and the multikinase FGFR inhibitor lenvatinib (10 mg p.o. daily); three (50%) achieved a PR [9 (ovarian), 12 (biliary), and 52+ months (osteosarcoma)]. Palbociclib and lenvatinib were tolerated well. CONCLUSIONS: FGF/FGFR alterations portend a poor prognosis and are frequently accompanied by pathogenic co-aberrations. Malignancies harboring co-alterations that activate both cyclin and FGFR pathways can be co-targeted by CDK4/6 and FGFR inhibitors.

Gastrointestinal stromal tumour lacking mutations in the KIT and PDGFRA genes in a cat.

Molecular subtyping in gastrointestinal stromal tumours is a useful method for predicting the efficacy of treatment using tyrosine kinase inhibitors in humans. However, owing to the paucity of reports on mutational analyses, the association between genetic mutations and the therapeutic response to tyrosine kinase inhibitors remains unclear in feline gastrointestinal stromal tumours. In this report, we describe the case of a cat with a gastrointestinal stromal tumour which was unresponsive to tyrosine kinase inhibitors. A mutational analysis revealed that the cat lacked mutations in both the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes. Our findings are consistent with the fact that KIT/PDGFRA wild-type gastrointestinal stromal tumours are less responsive to tyrosine kinase inhibitors in humans. This signifies the need for further evaluation and possibly individualised treatment for gastrointestinal stromal tumours in cats on the basis of mutational analyses.

Epidemiology and clinical characteristics of childhood TB identified using active and passive case finding.

BACKGROUND: Childhood TB cases can be found using passive case finding (PCF), i.e., by diagnosing children presenting with symptoms, or using active case finding (ACF), i.e., by identifying children with TB through contact tracing. Our study determined epidemiologic, clinical, and radiographic differences between these groups.DESIGN/METHODS: Retrospective cohort study of children aged 0-19 years diagnosed with TB from January 1, 2012 to December 31, 2019 at a U.S. TB clinic, comparing clinical, radiographic, microbiologic, and epidemiological characteristics of children identified using PCF and ACF.RESULTS: Of 178 eligible patients, 99 (55.6%) were diagnosed using PCF. Children identified using PCF were older (mean 8.9 vs. 6.1 years, P = 0.003), more often non-US-born (OR 2.29, 95% CI 1.12-4.67), had more extrapulmonary disease (44.4% vs. 3.8%, OR 20.27, 95% CI 5.98-68.64) and severe intrathoracic findings (39.4% vs. 10.1%, OR 5.77, 95% CI 2.50-13.29). Children identified using ACF were often asymptomatic, had isolated hilar/mediastinal adenopathy, but had more availability of drug susceptibility data from a link to a source case.CONCLUSION: Children identified using PCF had more severe manifestations, while those identified using ACF had greater availability of drug susceptibility data. Clinicians should be aware that clinical and radiographic presentations in children identified using PCF and those identified using ACF differ, and that the latter may be eligible for shorter treatment regimens.

A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903.

BACKGROUND: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. PATIENTS AND METHODS: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. RESULTS: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). CONCLUSIONS: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.

Usefulness of an artificial neural network for a beginner to achieve similar interpretations to an expert when examining myocardial perfusion images.

This study examined whether using an artificial neural network (ANN) helps beginners in diagnostic cardiac imaging to achieve similar results to experts when interpreting stress myocardial perfusion imaging (MPI). One hundred and thirty-eight patients underwent stress MPI with Tc-labeled agents. An expert and a beginner interpreted stress/rest MPI with or without the ANN and the results were compared. The myocardium was divided into 5 regions (the apex; septum; anterior; lateral, and inferior regions), and the defect score of myocardial blood flow was evaluated from 0 to 4, and SSS, SRS, and SDS were calculated. The ANN effect, defined as the difference in each of these scores between with and without the ANN, was calculated to investigate the influence of ANN on the interpreters' performance. We classified 2 groups (insignificant perfusion group and significant perfusion group) and compared them. In the same way, classified 2 groups (insignificant ischemia group and significant ischemia group) and compared them. Besides, we classified 2 groups (normal vessels group and multi-vessels group) and compared them. The ANN effect was smaller for the expert than for the beginner. Besides, the ANN effect for insignificant perfusion group, insignificant ischemia group and multi-vessels group were smaller for the expert than for the beginner. On the other hand, the ANN effect for significant perfusion group, significant ischemia group and normal vessels group were no significant. When interpreting MPI, beginners may achieve similar results to experts by using an ANN. Thus, interpreting MPI with ANN may be useful for beginners. Furthermore, when beginners interpret insignificant perfusion group, insignificant ischemia group and multi-vessel group, beginners may achieve similar results to experts by using an ANN.

Optimization of laser-target parameters for the production of stable lithium beam.

A laser ion source coupled with a radio frequency quadrupole linac accelerator is being proposed as a suitable system for the production of a low energy, high-current stable lithium beam. In order to maximize the lithium yield, plasmas generated by laser ablation of different materials based on lithium (Li, LiOH, and LiNbO3) have been characterized by using a Faraday cup and an electrostatic ion analyzer in the time of flight configuration. A wide range of laser power density has been investigated (109-1012 W/cm2) using two Nd:YAG lasers operating at different wavelengths (1064 nm and 532 nm), pulse durations (6 ns and 17 ns), and maximum energies (1400 mJ and 210 mJ). This paper outlines the pros and cons of the investigated materials by studying how the ion energy, yields, and charge state distributions are modified when the laser power density is changed. Considerable attention has been paid to the higher charge states of oxygen, which may occur with the same mass-to-charge ratio of Li3+. The analysis has evidenced that LiNbO3 represents a valid target since it allows minimizing the O6+/7Li3+ ratio down to 2.5% by using a laser power density of 1.8 × 1010 W/cm2. For such a condition, a Li3+ current of 1.4 mA/cm2 has been measured.

Feasibility study of a compact heavy ion source for investigation of laboratory magnetospheric plasma.

We are developing a laser ion source to provide a high brightness multi-charged heavy ion beam as a part of the heavy ion beam probe system, which will be used to diagnose plasma potential in the Ring Trap 1 device at the University of Tokyo. As a probe beam, Nb2+ was selected, and a detailed laser irradiation condition was explored. It was found that the laser power density of 1.2 × 109 W/cm2 gives the maximum particle number of Nb2+ per laser energy from a niobium foil target. Essential ablation plasma parameters to design the laser ion source were also obtained. The expected beam current was more than 12 mA/cm2, with a pulse width of 3.1 µs at 200 mm away from the target.

96Zr beam production for isobar experiment in relativistic heavy ion collider.

To investigate the chiral magnetic effect, 96Zr and 96Ru beams were accelerated at the relativistic heavy ion collider (RHIC) during Run-18 at Brookhaven National Laboratory. The 96Zr beam was provided from the electron beam ion source (EBIS) injector, which consists of a laser ion source, an EBIS high charge state ion breeder, a 300 keV/u radio frequency quadrupole, and a 2 MeV/u interdigital H type drift tube linear accelerator (IH-DTL). The natural abundance of 96Zr is only 2.8% with about 50% of 90Zr. To obtain a sufficient beam current, Zr material enriched to about 60% of 96Zr was used. The only available form of the enriched material was zirconium oxide (ZrO2) powder, which was not well suited for a laser ion source target. We studied and established a sintering technique of the ZrO2 powder to make a solid sample which could be installed into the laser ion source. The singly charged Zr was produced in a laser ablation plasma, extracted, and delivered to the EBIS to be ionized further to 96Zr16+. We optimized the laser irradiation condition, the EBIS confinement time, and transport through the RF linacs to maximize the performance of the injector. The total number of shots provided from the laser ion source for injection into the EBIS was 489 910. The EBIS facility provided a 192 MeV stable beam of 96Zr16+ ions to the booster ring of alternating gradient synchrotron (AGS) for further acceleration and stripping in the AGS/RHIC complex, allowing for successful data acquisition at the Solenoidal Tracker at the RHIC.

Purification, Rheological Characterization, and Visualization of Viscous, Neutral, Hetero-exopolysaccharide Produced by Lactic Acid Bacteria.

Viscous exopolysaccharide (EPS)-producing lactic acid bacteria (LAB) have received increasing interest in the dairy industry because of their capability to improve the texture and mouthfeel of fermented dairy products. To date, enormous efforts have been made to reveal the relationship between texture and EPS production in fermented milk products such as yogurt. However, the structure-rheology relationship of EPSs themselves is not yet well understood due to their low yields in general and their wide variety of chemical structures. In this chapter, we describe common techniques for the purification, visualization, and rheological analysis of viscous EPSs produced by LAB.

Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation.

BACKGROUND AND PURPOSE: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. METHODS: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide 'probable' and 'possible' designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. RESULTS: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as 'probable' and 32 (39%) were diagnosed as 'possible,' leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled 'probable' or 'possible' to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. CONCLUSIONS: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

The RPMI-1640 vitamin mixture promotes bovine blastocyst development in vitro and downregulates gene expression of TXNIP with epigenetic modification of associated histones.

Diverse environmental conditions surrounding preimplantation embryos, including available nutrients, affect their metabolism and development in both short- and long-term manner. Thioredoxin-interacting protein (TXNIP) is a possible marker for preimplantation stress that is implicated in in vitro fertilization- (IVF) induced long-term DOHaD effects. B vitamins, as participants in one-carbon metabolism, may affect preimplantation embryos by epigenetic alterations of metabolically and developmentally important genes. In vitro-produced bovine embryos were cultured with or without Roswell Park Memorial Institute 1640 vitamin mixture, containing B vitamins and B vitamin-like substances, from day 3 after IVF and we evaluated blastocyst development and TXNIP messenger RNA (mRNA) expression in the blastocysts by reverse transcription-quantitative polymerase chain reaction. The degree of trimethylation of histone H3 lysine 27 (H3K27me3) at TXNIP promoter was examined semi-quantitatively by chromatin immunoprecipitation polymerase chain reaction. Total H3K27me3 were also compared between the groups by Western blot analysis. The vitamin treatment significantly increased the rates of blastocyst development (P<0.05) and their hatching (P<0.001) from the zona pellucida by day 8. The mRNA expression of TXNIP was lower (P<0.01) in blastocysts in the vitamin-mixture-treated group concomitant with higher (P<0.05) level of H3K27me3 of its promoter compared with the control group. The total H3K27me3 in the vitamin-mixture-treated group was also higher (P<0.01) than that in the control group. The epigenetic control of genes related to important metabolic processes during the periconceptional period by nutritional conditions in utero and/or in vitro may have possible implication for the developmental programming during this period that may impact the welfare and production traits of farm animals.

Stabilization of milk proteins in acidic conditions by pectic polysaccharides extracted from soy flour.

Pectic polysaccharides were extracted from soy flour at either room temperature (SPRT) or 121°C (SPH), and their abilities to stabilize milk proteins in acidic conditions were evaluated. Both SPRT and SPH were found to contain proteinaceous components that were difficult to dissociate from polysaccharide components using size exclusion chromatography, whereas the molar mass of the former was approximately twice that of the latter. Due to the higher molar mass, SPRT was expected to provide stronger steric effects to prevent aggregation between milk proteins in acidic conditions than SPH. Alkaline treatment of SPRT for breaking O-linkages between AA and monosaccharide residues decreased its molar mass by approximately 160 kDa, indicating that they contained naturally occurring conjugates of pectic and proteinaceous moieties. Particle size distributions in simulated acidified milk drink samples containing 0.2% SPRT or SPH showed monomodal distributions with median diameters of around 1.2 µm at pH 4. The presence of large protein aggregates (∼5 µm) was detected at 0.2% SPRT and pH 3.2, 0.6 to 0.8% SPRT and pH 4, or 0.2% SPH and pH 3.4. The presence of excess polysaccharide molecules unbound to proteins was detected at 0.2% SPRT and pH 3.2 to 3.4, 0.4 to 0.8% SPRT and pH 4, 0.2% SPH and pH 3.4 to 3.6, and 0.4 to 0.8% SPH and pH 4. The present results suggest that molecular characteristics of pectic polysaccharides vary depending on extraction conditions and hence their functional behavior.

Squatting-induced bilateral peroneal nerve palsy in a sewer pipe worker.

Compression neuropathy of the common peroneal nerve (CPN) at the fibula head is a common condition, but it has not attracted attention in working environments. Here, we report a 38-year-old sewer pipe worker who presented with bilateral CPN palsy following 6h working with a squatting posture in a narrow sewer pipe. During the work, he could not stretch his legs sufficiently because of the confined space. His symptoms deteriorated with repetition of the same work for 1 week. Motor nerve conduction study showed conduction block at the fibula head of bilateral CPNs, compatible with compression neuropathy at this lesion. Three months after cessation of work requiring the causative posture, his symptoms and neurophysiological abnormalities had resolved completely. Almost all seven of his co-workers presented transiently with similar and milder symptoms, although one showed CPN palsy for 6 months. Prolonged squatting posture in a confined space causes acute compression neuropathy at the fibula head in the CPN. More attention should be paid to 'confined space worker's compression neuropathy'.

Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation.

BACKGROUND AND PURPOSE: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated. METHODS: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. RESULTS: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18-78 years), the mean age at death was 53 years (range 23-84 years) and the mean disease duration was 6.8 years (range 1-29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158-11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype-genotype correlations. CONCLUSIONS: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

Effects of the conjugation of whey proteins with gellan polysaccharides on surfactant-induced competitive displacement from the air-water interface.

Whey proteins can be used to stabilize foams and emulsions against coalescence because of their ability to form viscoelastic films at the interface that resist film rupture on collision between colloidal particles. However, whey proteins are competitively displaced from the interface if small-molecule surfactants are added, leading to destabilization of the entire system. This is because surfactants are more effective in molecular packing at the interface, and they lower interfacial tension to a greater degree than whey proteins do, but their interfacial films are poor in viscoelasticity. We hypothesized that whey proteins would become more resistant to surfactant-induced competitive displacement if they were conjugated with network-forming polysaccharides. The protein moiety of the conjugate would be expected to enable its adsorption to the interface, and the polysaccharide moiety would be expected to form self-assembled networks, strengthening the interfacial film as a whole. In this study, whey proteins were conjugated with gellan polysaccharides using the Maillard reaction. Atomic force microscopy images of interfacial films formed by the whey protein-gellan conjugate at the air-water interface and transferred onto mica sheets using the Langmuir-Blodgett method revealed that gellan did form self-assembled networks at the interface and that interfacial films also contained a large number of unconjugated whey protein molecules. Following the addition of a small-molecule surfactant (Tween 20) to the sub-phase, surface pressure increased, indicating spontaneous adsorption of surfactants to the interface. Atomic force microscopy images showed decreases in interfacial area coverage by whey proteins as surface pressure increased. At a given surface pressure, the interfacial area coverage by whey protein-gellan conjugates was greater than coverage by unconjugated whey proteins, confirming that whey proteins became more resistant to surfactant-induced displacement after conjugation with gellan. Furthermore, gellan molecules added to the sub-phase after the formation of a monolayer of whey proteins at the air-water interface did not adsorb to the interfacial protein film. These results provide a molecular basis for designing interfacial structures to enhance the stability of colloidal systems.

Metastasis of extra-ampullary duodenal adenocarcinoma to the uterine cervix.

Secondary metastatic tumours of the uterine cervix are rare. There have been no reports of duodenal cancer metastasizing to the uterine cervix. Here we present a rare case of an extra-ampullary duodenal adenocarcinoma that has metastasized to the uterine cervix. The patient was a 71-year-old woman who had surgery for an extra-ampullary duodenal adenocarcinoma five years previously. Follow-up examination revealed a suspicious right ovarian mass and nodules in the cervix and posterior fornix of the vagina. Biopsies suggested squamous cell carcinoma in the cervix and adenocarcinoma in the fornix. Intraoperatively, the right ovary was enlarged and peritoneal disseminations were found in the pouch of Douglas and the sigmoid colon mesentery. Histopathology of the subsequent hysterectomy and bilateral salpingo-oophorectomy specimen revealed a cervical squamous cell carcinoma categorized as pT1b1. Adenocarcinoma infiltration into the ovaries, uterine cervix and vagina, with vascular involvement was detected. Immunohistochemistry revealed the tumour in the cervix and ovaries to be positive for CK7, MUC5AC and MUC6, and immunonegative for CK20, CDX2, Pax8, ER, MUC2 and CD10, similar to the original duodenal adenocarcinoma. This case illustrates the difficulty in making a preoperative diagnosis of metastatic adenocarcinoma in the uterine cervix with a coexisting primary cervical squamous cell carcinoma. The absence of atypia in cervical glandular cells and immunohistochemical profiling of the adenocarcinoma clusters helped to reach a final diagnosis. This is the first report of an extra-ampullary duodenal adenocarcinoma metastasis to the uterine cervix.