Activating mutations of the epidermal growth factor receptor gene (
) are a driving force for some lung adenocarcinomas. Several randomized phase III studies have revealed that treatment with first- ...or second-generation EGFR tyrosine kinase inhibitors (TKIs) results in an improved progression-free survival (PFS) compared to standard chemotherapy in chemonaive patients with advanced non⁻small cell lung cancer (NSCLC), selected based on the presence of
mutations. Patients treated with second-generation EGFR-TKIs have also shown an improved PFS relative to those treated with first-generation EGRF-TKIs. Osimertinib is a third-generation EGFR-TKI that still irreversibly inhibits the activity of EGFR after it has acquired the secondary T790M mutation that confers resistance to first- and second-generation drugs. Its efficacy has been validated for patients whose tumors have developed T790M-mediated resistance, as well as for first-line treatment of those patients with
mutation⁻positive NSCLC. Although there are five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) currently available for the treatment of
-mutated lung cancer, the optimal sequence for administration of these drugs remains to be determined. In this review, we addressed this issue with regard to maximizing the duration of the EGFR-TKI treatment.
Highlights • Afatinib, erlotinib, and gefitinib are available for EGFR mutation-positive NSCLC. • Severe rash and diarrhea were more frequent with afatinib treatment. • Severe hepatotoxicity was more ...frequent with gefitinib treatment.
•Novel coronavirus (SARS-Coronavirus-2:SARS-CoV-2) which emerged in Wuhan, China, has spread to multiple countries rapidly.•This is the first case of meningitis associated with SARS-CoV-2 who was ...brought in by ambulance.•The specific SARS-CoV-2 RNA was not detected in the nasopharyngeal swab but was detected in a CSF.•This case warns the physicians of patients who have CNS symptoms.
Novel coronavirus (SARS-Coronavirus-2:SARS-CoV-2) which emerged in Wuhan, China, has spread to multiple countries rapidly. We report the first case of meningitis associated with SARS-CoV-2 who was brought in by ambulance due to a convulsion accompanied by unconsciousness. He had never been to any foreign countries. He felt generalized fatigue and fever (day 1). He saw doctors nearby twice (day 2 and 5) and was prescribed Laninamivir and antipyretic agents, His family visited his home and found that he was unconsciousness and lying on the floor in his vomit. He was immediately transported to this hospital by ambulance (day 9). Under emergency transport, he had transient generalized seizures that lasted about a minute. He had obvious neck stiffness. The specific SARS-CoV-2 RNA was not detected in the nasopharyngeal swab but was detected in a CSF. Anti- HSV 1 and varicella-zoster IgM antibodies were not detected in serum samples. A brain MRI showed hyperintensity along the wall of right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting the possibility of SARS-CoV-2 meningitis. This case warns the physicians of patients who have CNS symptoms.
Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an ...immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting.
B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (
= 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8
tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry.
B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8
TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8
TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8
TILs and recovery of effector function. CD8
T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8
T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction.
B7-H3 expressed on tumor cells potentially circumvents CD8
-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs.
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The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear.
We retrospectively identified 138 patients with
...-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing.
The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (
= 0.0010). Whereas CD8
and FOXP3
TIL densities were significantly lower after EGFR-TKI treatment than before, CD8
TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp,
= 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months,
= 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months.
EGFR-TKI treatment was associated with changes in the TME of
-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.
The urothelium is a sensory structure that contributes to mechanosensation in the urinary bladder. Here, we provide evidence for a critical role for the Piezo1 channel, a newly identified ...mechanosensory molecule, in the mouse bladder urothelium. We performed a systematic analysis of the molecular and functional expression of Piezo1 channels in the urothelium. Immunofluorescence examination demonstrated abundant expression of Piezo1 in the mouse and human urothelium. Urothelial cells isolated from mice exhibited a Piezo1-dependent increase in cytosolic Ca2+ concentrations in response to mechanical stretch stimuli, leading to potent ATP release; this response was suppressed in Piezo1-knockdown cells. In addition, Piezo1 and TRPV4 distinguished different intensities of mechanical stimulus. Moreover, GsMTx4, an inhibitor of stretch-activated channels, attenuated the Ca2+ influx into urothelial cells and decreased ATP release from them upon stretch stimulation. These results suggest that Piezo1 senses extension of the bladder urothelium, leading to production of an ATP signal. Thus, inhibition of Piezo1 might provide a promising means of treating bladder dysfunction.
The Piezo1 channel was recently identified as a genuine mechanosensor in mammalian cells.
Urothelial cells exhibited a Piezo1-dependent increase in cytosolic Ca2+ concentrations in response to mechanical stretch stimuli, leading to ATP release.
Piezo1 senses extension of the bladder urothelium, which is converted into an ATP signal.
Inhibition of Piezo1 might provide a new treatment for bladder dysfunction.
Palindromes are important objects in strings which have been extensively studied from combinatorial, algorithmic, and bioinformatics points of views. It is known that the length of the longest ...palindromic substrings (LPSs) of a given string T of length n can be computed in O(n) time by Manacher's algorithm 12. In this paper, we consider the problem of finding the LPS after the string is edited. We present an algorithm that uses O(n) time and space for preprocessing, and answers the length of the LPSs in O(log(min{σ,logn})) time after a single character substitution, insertion, or deletion, where σ denotes the number of distinct characters appearing in T. We also propose an algorithm that uses O(n) time and space for preprocessing, and answers the length of the LPSs in O(ℓ+loglogn) time, after an existing substring in T is replaced by a string of arbitrary length ℓ.
Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of ...tumors that express HER2 protein in the absence of HER2 amplification. fam‐ trastuzumab deruxtecan (DS‐8201a) is a novel antibody–drug conjugate composed of the anti‐HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials. We here show that the antitumor activity of fam‐ trastuzumab deruxtecan is dependent on the expression level of HER2 protein in colorectal cancer (CRC) cell lines negative for HER2 amplification. We established isogenic CRC cell lines that express various levels of HER2 protein in the absence of HER2 amplification, and we found that cells that express HER2 at a high level were sensitive to fam‐ trastuzumab deruxtecan but not to conventional HER2‐targeted therapies. Furthermore, fam‐ trastuzumab deruxtecan manifested a bystander killing effect both in vitro and in vivo, with cells essentially negative for HER2 expression also being killed in the presence of HER2‐expressing cells, an effect that has the potential to overcome heterogeneity of HER2 expression in CRC tumors. Our results thus suggest that fam‐ trastuzumab deruxtecan warrants further study as a potential treatment for CRC tumors that express HER2 protein in the absence of HER2 amplification.
What's new?
HER2‐targeted therapies have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for tumors that express HER2 in the absence of HER2 amplification. fam‐ trastuzumab deruxtecan (DS‐8201a) is a novel antibody‐drug conjugate composed of the anti‐HER2 antibody and the topoisomerase I inhibitor. Here, DS‐8201a showed efficacy on colorectal cancer (CRC) cell lines that express HER2 in the absence of HER2 amplification. Furthermore, fam‐ trastuzumab deruxtecan exhibited a bystander killing effect in co‐culture models of HER2‐expressing cells and HER2‐negative cells. The results may offer a new treatment option against CRC according to HER2 expression levels.
In this paper, we propose a new dynamic compressed index of O(w) space for a dynamic text T, where w=O(min(zlogNlog∗M,N)) is the size of the signature encoding of T, z is the size of the Lempel–Ziv77 ...(LZ77) factorization of T, N is the length of T, and M≥N is the maximum length of T. Our index supports searching for a pattern P in T in O(|P|fA+logwlog|P|log∗M(logN+log|P|log∗M)+occlogN) time and insertion/deletion of a substring of length y in O((y+logNlog∗M)logwlogNlog∗M) time, where occ is the number of occurrences of P in T and fA=O(min{loglogMloglogwlogloglogM,logwloglogw}). Also, we propose a new space-efficient LZ77 factorization algorithm for a given text T, which runs in O(NfA+zlogwlog3N(log∗N)2) time with O(w) working space.
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