Anaplastic lymphoma kinase (
) rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on ...the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare
-rearranged tumors.
Between April 2012 and April 2019, clinical outcomes and characteristics of patients with
-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression.
We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare
fusions, namely,
K and
, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib.
This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with
-rearranged nonlung solid tumors.
Anorectal function deteriorates with age. The diagnostic performance of the endoscopic pressure study integrated system (EPSIS), an endoscopic carbon dioxide (CO
) insufflation stress test of the ...lower esophageal sphincter has been previously evaluated as a diagnostic tool for gastroesophageal reflux disease. We aimed to evaluate the applicability of EPSIS in improving anorectal function. We hypothesized that EPSIS can be applied to the diagnosis of lower gastrointestinal tract disorders.
This was a pilot, single-center, retrospective study using prospectively collected data between December 2021 and March 2022. It was designed to evaluate the differences in EPSIS rectal pressure measurements between older (≥80 years) and younger (<80 years) patients. At the end of the screening colonoscopy, the colonoscope was fixed in a retroflex position. When bowel movement was observed, CO
was insufflated to the point where gas leakage occurred through the anus. The measured maximum pressure was defined as EPSIS-rectal pressure max (EPSIS-RP max) and compared between the groups.
Overall, 30 patients were included and examined. The median ages of the <80 and ≥80 years' groups were 53 (range: 27-79) and 82 (range: 80-94) years, respectively, with corresponding median measured EPSIS-RP max of 18.7 (range: 8.5-30.2) and 9.8 (range: 5.4-22.3) mmHg (P<0.001).
Measurement of maximum rectal pressure illustrates the age-related decline in physiological anorectal function. Future studies should consider a loading test using EPSIS to quantify the decline in anorectal function and use it as a routine tool for screening and adjunctive diagnosis of anorectal hypofunction.
Hepatitis B and C (HBV and HCV) testing has been performed in Japan since 2002 and is subsidized by central and prefectural governments. A follow-up program for HBV- or HCV-infected persons was ...started at that time in Ishikawa Prefecture. This study analyzed the long-term follow-up data from this program. In total, 1029 participants in the Ishikawa Hepatitis Follow-up Program (HBV-infected, n = 535; HCV-infected, n = 494) were enrolled. Clinical data between the first visit and the most recent visit by March 2019 were collected. In the HBV-infected group, 384 persons (71.8%) were asymptomatic carriers, 133 (24.9%) developed chronic hepatitis, 15 (2.8%) developed compensated liver cirrhosis, and 3 (0.6%) developed decompensated liver cirrhosis. Ninety (16.8%) were treated with nucleotide/nucleoside analogs. Sixteen (3.0%) developed liver cancer. In the HCV-infected group, 427 persons (86.4%) developed chronic hepatitis, 46 (9.3%) developed compensated liver cirrhosis, and 21 (4.3%) developed decompensated liver cirrhosis. Forty-eight (9.7%) developed liver cancer. Three hundred and seventy-eight (76.5%) received antiviral therapy (a direct-acting antiviral in 166, interferon-based treatment followed by a direct-acting antiviral in 73, and interferon-based treatment in 139). The subsidy system was used by 270 persons (71.4%). Sustained virological response was confirmed in 340 persons (68.8%). A higher FIB-4 index at the first visit was a significant risk factor for liver cancer in HBV-infected and HCV-infected persons. The Ishikawa Hepatitis Follow-up Program has revealed the clinical course of HBV and HCV infection in community-dwelling individuals. The results will be used for micro-elimination at a prefectural level.
► Clostridium botulinum neurotoxin forms a progenitor complex with hemagglutinins. ► X-ray structures of the hemagglutinin/oligosaccharides complexes were determined. ► α2–3-Sialylated ...oligosaccharide bound to hemagglutinin tightly. ► α2–6-Sialylated oligosaccharide bound to hemagglutinin with a low occupancy. ► A binding assay also showed a higher affinity for α2–3-sialylated oligosaccharide.
Clostridium botulinum produces the botulinum neurotoxin, forming a large complex as progenitor toxins in association with non-toxic non-hemagglutinin and/or several different hemagglutinin (HA) subcomponents, HA33, HA17 and HA70, which bind to carbohydrate of glycoproteins from epithelial cells in the infection process. To elucidate the carbohydrate recognition mechanism of HA70, X-ray structures of HA70 from type C toxin (HA70/C) in complexes with sialylated oligosaccharides were determined, and a binding assay by the glycoconjugate microarray was performed. These results suggested that HA70/C can recognize both α2–3- and α2–6-sialylated oligosaccharides, and that it has a higher affinity for α2–3-sialylated oligosaccharides.
Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE
−/−Angptl 4
−/− mice to study the ...effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE
−/−Angptl 4
−/− mice compared with and ApoE
−/−Angptl 4
+/+ mice. There was a significant (75
±
12%) reduction in atherosclerotic lesion size in ApoE
−/−Angptl 4
−/− mice compared with ApoE
−/− Angptl 4
+/+ mice. Peritoneal macrophages, isolated from Angptl 4
−/− mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4
+/+ mice. Thus, genetic knockout of Angptl 4 protects ApoE
−/− mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells
in vitro.
α-Catenin is a filamentous actin (F-actin) binding protein that links the classical cadherin–catenin complex to the actin cytoskeleton at adherens junctions (AJs). Its C-terminal F-actin binding ...domain is required for regulating the dynamic interaction between AJs and the actin cytoskeleton during tissue development. Thus, obtaining the molecular details of this interaction is a crucial step towards understanding how α-catenin plays critical roles in biological processes, such as morphogenesis, cell polarity, wound healing and tissue maintenance. Here we report the backbone atom (
1
H
N
,
15
N,
13
C
α
,
13
C
β
and
13
C′) resonance assignments of the C-terminal F-actin binding domain of αN-catenin.
► Caloric restriction (CR) reduced the weight of ob/ob mice. ► CR reduced ER stress markers such as phosphorylated PERK and eIF2α in ob/ob mice. ► CR reduced JNK and IRS-1 serine phosphorylation in ...ob/ob mice. ► CR improved glucose tolerance and hepatic insulin action in ob/ob mice. ► Reduction in ER stress by CR was comparable to that by a chemical chaperone PBA.
Endoplasmic reticulum (ER) stress plays a crucial role in the development of insulin resistance and diabetes. Although caloric restriction (CR) improves obesity-related disorders, the effects of CR on ER stress in obesity remain unknown. To investigate how CR affects ER stress in obesity, ob/ob mice were assigned to either ad libitum (AL) (ob-AL) or CR (ob-CR) feeding (2g food/day) for 1–4weeks. The body weight (BW) of ob-CR mice decreased to the level of lean AL-fed littermates (lean-AL) within 2weeks. BW of lean-AL and ob-CR mice was less than that of ob-AL mice. The ob-CR mice showed improved glucose tolerance and hepatic insulin action compared with ob-AL mice. Levels of ER stress markers such as phosphorylated PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2α and the mRNA expression of activating transcription factor 4 were significantly higher in the liver and epididymal fat from ob-AL mice compared with lean-AL mice. CR for 2 and 4weeks significantly reduced all of these markers to less than 35% and 50%, respectively, of the levels in ob-AL mice. CR also significantly reduced the phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun NH2-terminal kinase (JNK) in ob/ob mice. The CR-mediated decrease in PERK phosphorylation was similar to that induced by 4-phenyl butyric acid, which reduces ER stress in vivo. In conclusion, CR reduced ER stress and improved hepatic insulin action by suppressing JNK-mediated IRS-1 serine-phosphorylation in ob/ob mice.
We attempted to use feathers for the production of activated carbon (AC). A water-soluble resol-type phenolic resin was hybridized to prevent the liquefaction of the feathers and to control the ...graphitization degree of charcoal. The hybridization could effectively increase the yield of charcoal over 30% and maintained the graphitization degree at approximately 0.1, suitable for the production of AC. The Brunauer–Emmett–Teller (BET) surface area and the iodine-adsorption capacity of hybrid charcoal-based AC were 706m2/g and 550mg/g, respectively, which were 1.7-1.8 times greater than those of the feather-based AC at a similar activation level.
Babesia bovis, B. bigemina, Trypanosoma evansi, and Anaplasma marginale infections cause serious diseases in cattle, and are primarily transmitted by arthropod vectors (ticks for B. bovis, B. ...bigemina, and A. marginale and various types of flies for T. evansi). In the last few years, there have been many reports of a high prevalence of certain protozoan infections in northern Egypt, but no accurate or adequate data are available for the southern regions. Therefore, in this study, we screened for evidence of such diseases in economically important cattle species using serum samples. The seroprevalence of protozoan infections in cattle was determined with enzyme-linked immunosorbent assays using species-specific diagnostic antigens. In a total of 301 cattle serum samples, 27 (9.0%), 100 (33.2%), and 127 (42.2%) were positive for specific antibodies against B. bovis, B. bigemina, and T. evansi, respectively. Sera from 90 cattle were also tested for antibodies against A. marginale, and 25 (28%) of them were positive. The highest coinfection rate occurred for B. bigemina and T. evansi with 10.6% (32/301). When age, sex, locality, and breeding system were investigated as predisposing factors, bulls and cattle <3 years old were more vulnerable to B. bovis infections than older animals, and geographic location affected the B. bigemina infection rate. The recorded seroprevalence of hemoprotozoan parasites and A. marginale in cattle suggests that these diseases have the potential capacity to detrimentally affect meat and milk production in southern Egypt.
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