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.
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.
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%.
Under the national registration tracking system, Taiwan's high-cost drug policy has enabled access to new medicines and maximized patient benefits.
AbstractDiving upon pullout of an installed anchor leads to an increase in embedment depth and, hence, capacity under operational loadings. It is particularly critical for dynamically installed ...anchors (DIAs) in calcareous sediments where the embedment depth is generally relatively shallow. This paper proposes a novel fish DIA featuring an elliptically shaped shaft, which reduces hydrodynamic drag resistance. Every cross section of the anchor shaft is elliptical, and the widest part is in the middle. The shaft is shaped to be thicker near the head to lower the mass centroid and increase its diving potential. The padeye is fitted perpendicularly to the wider part of the shaft, so that the maximum resistance area can be mobilized during pullout loading. The dynamic installation and monotonic pullout performance of the fish DIA in calcareous silt were assessed through a series of beam centrifuge tests at 133.3 times Earth’s gravity, varying the drop height (hence the impact velocity), reconsolidation period after installation and load inclination angle at the mudline. The anchor tip embedment depths of 1.02–1.42 times the anchor length lay in the range for OMNI-Max and torpedo DIAs in calcareous silt. A dimensionless embedment depth–based model, total energy–based models, and a conventional shear resistance model were found to be adequate for the prediction of embedment depths. The tracked anchor trajectory confirmed that the fish DIA dove under inclined mudline loading (θ0<45°), as opposed to being pulled out for torpedo and OMNI-Max DIAs. The normalized vertical and horizontal holding capacities of the fish DIA were respectively 4.0 and 5.6 times those of a four-fin torpedo DIA.
The translation of high-throughput gene expression data into biologically meaningful information remains a bottleneck. We developed a novel computational algorithm, PATHOME, for detecting ...differentially expressed biological pathways. This algorithm employs straightforward statistical tests to evaluate the significance of differential expression patterns along subpathways. Applying it to gene expression data sets of gastric cancer (GC), we compared its performance with those of other leading programs. Based on a literature-driven reference set, PATHOME showed greater consistency in identifying known cancer-related pathways. For the WNT pathway uniquely identified by PATHOME, we validated its involvement in gastric carcinogenesis through experimental perturbation of both cell lines and animal models. We identified HNF4α-WNT5A regulation in the cross-talk between the AMPK metabolic pathway and the WNT signaling pathway, and further identified WNT5A as a potential therapeutic target for GC. We have demonstrated PATHOME to be a powerful tool, with improved sensitivity for identifying disease-related dysregulated pathways.
FLJ10540, originally identified as a microtubule-associated protein, induces cell proliferation and migration during tumorigenesis via the formation of FLJ10540-PI3K complex and enhancement of PI3K ...kinase activity. Interestingly, activation of PI3K/Akt cascade, leading to upregulation of nitric oxide synthase II (NOS II)/peroxynitrite signaling in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone, mediates the impairment of brain stem cardiovascular regulation induced by the pesticide mevinphos. We evaluated the hypothesis that upregulation of FLJ10540 in the RVLM is upstream to this repertoire of signaling cascade that underpins mevinphos-induced circulatory depression. Microinjection bilaterally of mevinphos (10nmol) into the RVLM of anesthetized Sprague–Dawley rats induced a progressive hypotension that was accompanied by an increase (Phase I), followed by a decrease (Phase II) of an experimental index for baroreflex-mediated sympathetic vasomotor tone. There was augmentation in FLJ10540 mRNA in the RVLM or FLJ10540 protein in RVLM neurons, both of which were causally and temporally related to an augmentation of binding between the catalytic subunit (p110) and regulatory subunit (p85) of PI3K, phosphorylation of Akt at Thr308 site, and NOS II, superoxide or peroxynitrite level in the RVLM. Immunoneutralization of FJL10540 in the RVLM significantly antagonized those biochemical changes, and blunted the progressive hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during mevinphos intoxication. We conclude that upregulation of FLJ10540 in the RVLM elicits impairment of brain stem cardiovascular regulation that underpins circulatory depression during mevinphos intoxication via activation of PI3K/Akt/NOS II/peroxynitrite signaling cascade in the RVLM.
This article reports an improved independent measurement of neutrino mixing angle θ13 at the Daya Bay Reactor Neutrino Experiment. Electron antineutrinos were identified by inverse β-decays with the ...emitted neutron captured by hydrogen, yielding a data-set with principally distinct uncertainties from that with neutrons captured by gadolinium. With the final two of eight antineutrino detectors installed, this study used 621 days of data including the previously reported 217-day data set with six detectors. The dominant statistical uncertainty was reduced by 49%. Intensive studies of the cosmogenic muon-induced 9Li and fast neutron backgrounds and the neutron-capture energy selection efficiency, resulted in a reduction of the systematic uncertainty by 26%. The deficit in the detected number of antineutrinos at the far detectors relative to the expected number based on the near detectors yielded sin22θ13=0.071±0.011 in the three-neutrino-oscillation framework. The combination of this result with the gadolinium-capture result is also reported.
Extensive use of current anti-coccidial drugs together with drug resistance and residue has raised concerns about public health and poultry development. Here, we studied the anti-coccidial properties ...of Bidens pilosa. A phytochemical approach was developed for analysis of B. pilosa utilized as a feed additive. The protective effects of B. pilosa supplemented chicken diet were evaluated chickens infected with Eimeria tenella. B. pilosa, at doses of 0.5%, 1% and 5% of the chicken diet, significantly protected against E. tenella as measured by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology in chickens. Finally, drug resistance of E. tenella to B. pilosa was assessed in chickens using the anti-coccidial index. This index showed that B. pilosa induced little, if any, drug resistance to Eimeria in chickens. Collectively, this work suggests that B. pilosa may serve as a novel, natural remedy for coccidiosis with low drug resistance in chickens.
The
csrRS
two-component regulatory system is an important element in the pathogenesis of group A
Streptococcus
(GAS). The main goal of this study is to understand the association between
csrRS
...polymorphisms and GAS infection. We sequenced the
csrRS
genes from 172 clinical isolates, including 81 invasive and 91 noninvasive isolates, and then employed phylogenetic analyses to determine the consequences of the
csrRS
polymorphisms. In total, 13 and 26 polymorphic loci were detected in the
csrR
and
csrS
genes, respectively. These polymorphisms constituted 14
csrR
and 25
csrS
alleles, producing two CsrR and seven CsrS variants, respectively. Three invasive isolates contained an indel in
csrS
, but no indel was identified in
csrR
. The frequency and distribution of polymorphisms in
csrR
and
csrS
was significantly different between the invasive and noninvasive infection isolates (
p
< 0.001). For CsrR, only one noninvasive isolate was identified to have a V29I mutation. The amino acid substitutions in CsrS included S32P (0.6 %), E265G (0.6 %), E265K (0.6 %), I332V (1.7 %), and N498K (82.6 %). Isolates with an N498K single mutation were more likely to be associated with invasive infections (
p
< 0.001). The dN/dS ratio indicated that both
csrR
and
csrS
were under purifying selection. The fixation index suggested a moderate evolutionary differentiation of the
csrR
and
csrS
alleles between invasive and noninvasive isolates. The identification of these genetic differences within the
csrRS
loci will provide a better understanding of the pathogenesis of GAS.
The limited sensitivity of serological tests for mycobacterial antigens has encouraged the development of a nanoparticle probe specific for the extrapulmonary form of Mycobacterium tuberculosis ...(Mtb). We developed an innovative probe comprised of super-paramagnetic iron oxide (SPIO) nanoparticles conjugated with Mtb surface antibody (MtbsAb-nanoparticles) to provide ultrasensitive imaging of biomarkers involved in extrapulmonary Mtb infection. MtbsAb-nanoparticles were significantly conjugated with Mtb bacilli. The extent of contrast enhancement reduction on magnetic resonance imaging (MRI) for Mtb and human monocytic THP1 cells was proportional to the concentration of MtbsAb-nanoparticles. When MtbsAb-nanoparticles were intravenously injected into mice bearing Mtb granulomas, the granulomatous site showed a 14-fold greater reduction in signal intensity enhancement on T2-weighted MR images compared with an opposing site that received PBS injection. Mtb sAb-nanoparticles represent a new non-invasive technology for the diagnosis of extrapulmonary Mtb.
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