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The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates β-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-β signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis. How aging induces aortic aneurysm and dissection (AAD) remains unclear. Here, the authors show that aging induces miR-1204 to inhibit MYLK, promoting vascular smooth muscle cells to acquire senescence-associated secretory phenotype, resulting in vascular inflammation, and the aggravation of AAD formation.

Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.

A bstract The rare radiative B -meson decay B − → γ ℓ − v ¯ and the radiative Higgs-boson decay h → γγ mediated by light-quark loops both receive large logarithmic corrections in QCD, which can be resummed using factorization theorems derived in soft-collinear effective theory. In these factorization theorems the same radiative jet function appears, which is a central object in the study of factorization beyond the leading order in scale ratios. We calculate this function at two-loop order both in momentum space and in a dual space, where its renormalization-group evolution takes on a simpler form. We also derive the two-loop anomalous dimension of the jet function and present the exact solution to its evolution equation at two-loop order. Another important outcome of our analysis is the explicit form of the two-loop anomalous dimension of the B -meson light-cone distribution amplitude in momentum space.

A bstract It is by now well known that, at subleading power in scale ratios, factorization theorems for high-energy cross sections and decay amplitudes contain endpoint-divergent convolution integrals. The presence of endpoint divergences hints at a violation of simple scale separation. At the technical level, they indicate an unexpected failure of dimensional regularization and the MS ¯ subtraction scheme. In this paper we start a detailed discussion of factorization at subleading power within the framework of soft-collinear effective theory. As a concrete example, we factorize the decay amplitude for the radiative Higgs-boson decay h → γγ mediated by a b -quark loop, for which endpoint-divergent convolution integrals require both dimensional and rapidity regulators. We derive a factorization theorem for the decay amplitude in terms of bare Wilson coefficients and operator matrix elements. We show that endpoint divergences caused by rapidity divergences cancel to all orders of perturbation theory, while endpoint divergences that are regularized dimensionally can be removed by rearranging the terms in the factorization theorem. We use our result to resum the leading double-logarithmic corrections of order α s n ln 2 n + 2 − M h 2 / m b 2 to the decay amplitude to all orders of perturbation theory.

transcription factors ( ) are a family of transcription factors involved in cell proliferation, differentiation, and apoptosis. Their important roles in the development and metastasis of breast carcinoma (BC) have been discovered by previous in vitro and in vivo studies. Yet, expressions and distinct prognostic values of these eight in human BC remain unclear in many respects. In this study, we aimed to reveal their roles in BC through analyzing the transcription and survival data of the in BC patients from four online databases including ONCOMINE, Breast Cancer Gene-Expression Miner v4.1, cBioPortal for Cancer Genomics, and Kaplan-Meier Plotter. We found the overexpression of in BC tissues compared with normal breast tissues, except for . Higher expression levels of , except for and , were associated with higher levels of Scarff-Bloom-Richardson grade of BC. Alterations of were found to be significantly correlated with poorer overall survival of BC patients. Through plotting the survival curve in the Kaplan-Meier Plotter, it was found that higher mRNA levels of , , , and were associated with poorer relapse-free survival in all BC patients, indicating that they are potential targets for individualized treatments of BC patients. Conversely, higher mRNA expression level of predicted better RFS in BC patients, suggesting as a new biomarker for BC prognosis. Considering currently available limited evidence, further studies need to be performed to investigate the roles of in BC.

Oxaliplatin-induced chronic painful neuropathy is the most common dose-limiting adverse event that negatively affects cancer patients’ quality of life. However, the underlying molecular mechanisms are still unclear. In the present study, we found that the intraperitoneal administration of oxaliplatin at 4 mg/kg for five consecutive days noticeably upregulated the expression of CXC motif ligand 12 (CXCL12) in the dorsal root ganglion, and the intrathecal injection of an anti-CXCL12 neutralizing antibody or CXCL12 siRNA attenuated the mechanical allodynia and thermal hyperalgesia induced by oxaliplatin. We also found that the signal transducers and transcription activator 3 (STAT3) was activated in the dorsal root ganglion, and inhibition of STAT3 with S3I-201 or the injection of AAV-Cre-GFP into STAT3flox/flox mice prevented the upregulation of CXCL12 expression in the dorsal root ganglion and chronic pain following oxaliplatin administration. Double-label fluorescent immunohistochemistry findings also showed that p-STAT3 was mainly localized in CXCL12-positive cells in the dorsal root ganglion. Furthermore, the results of a chromatin immunoprecipitation assay revealed that p-STAT3 might be essential for oxaliplatin-induced CXCL12 upregulation via binding directly to the specific position of the CXCL12 gene promoter. Finally, we found that cytokine TNF-α and IL-1β increases mediated the STAT3 activation following oxaliplatin treatment. Taken together, these findings suggested that the upregulation of CXCL12 via TNF-α/IL-1β–dependent STAT3 activation contributes to oxaliplatin-induced chronic pain.

A bstract We derive a factorization theorem for the Higgs-boson production amplitude in gluon-gluon fusion induced by a light-quark loop, working at next-to-leading power in soft-collinear effective theory. The factorization is structurally similar to that obtained for the h → γγ decay amplitude induced by a light-quark loop, but additional complications arise because of external color charges. We show how the refactorization-based subtraction scheme developed in previous work leads to a factorization theorem free of endpoint divergences. We use renormalization-group techniques to predict the logarithmically enhanced terms in the three-loop gg → h form factor of order α s 3 ln k − M h 2 / m b 2 with k = 6, 5, 4, 3. We also resum the first three towers of leading logarithms, α s n ln 2 n − k − M h 2 / m b 2 with k = 0, 1, 2, to all orders of perturbation theory.

A bstract Building on the recent derivation of a bare factorization theorem for the b -quark induced contribution to the h → γγ decay amplitude based on soft-collinear effective theory, we derive the first renormalized factorization theorem for a process described at subleading power in scale ratios, where λ = m b / M h « 1 in our case. We prove two refactorization conditions for a matching coefficient and an operator matrix element in the endpoint region, where they exhibit singularities giving rise to divergent convolution integrals. The refactorization conditions ensure that the dependence of the decay amplitude on the rapidity regulator, which regularizes the endpoint singularities, cancels out to all orders of perturbation theory. We establish the renormalized form of the factorization formula, proving that extra contributions arising from the fact that “endpoint regularization” does not commute with renormalization can be absorbed, to all orders, by a redefinition of one of the matching coefficients. We derive the renormalization-group evolution equation satisfied by all quantities in the factorization formula and use them to predict the large logarithms of order αα s 2 L k in the three-loop decay amplitude, where L = ln − M h 2 / m b 2 and k = 6 , 5 , 4 , 3. We find perfect agreement with existing numerical results for the amplitude and analytical results for the three-loop contributions involving a massless quark loop. On the other hand, we disagree with the results of previous attempts to predict the series of subleading logarithms ∼ αα s n L 2 n + 1 .

Due to the unsatisfactory robustness of current predictive biomarkers in many cases, application of immunotherapy in advanced cancers with limited treatment options, such as stage IV intrahepatic cholangiocarcinoma (ICC), was quite common. Hence, strategies to enhance the therapeutic effect of immunotherapy or to extend the scope of potential beneficial patients were urgently needed. Combination of radiotherapy and anti-programmed death receptor-1 (PD-1) immunotherapy was a promising one, since they were found to have a synergistic anti-tumor effect in animal models and a couple of patients. We here present a 68-years-old male with chemotherapy-intolerable stage IV ICC, whose primary tumor had low PD-L1 expression level, scarce CD8+ cells in tumor microenvironment, high microsatellite instability (MSI), and high tumor mutation burden (TMB). These biomarkers showed a conflicting prediction of the treatment response and clinical benefit of anti-PD-1 immunotherapy. Combination therapy of anti-PD-1 immunotherapy and radiotherapy was adopted as first-line treatment for the patient. After six cycles of immunotherapy, shrinkage of the primary liver tumor and metastatic lymph nodes happened, alongside with new lung metastasis, which indicated a mixed response. Radiotherapy was then administered to both the liver and lung lesions, accompanied with continued immunotherapy. The combined therapy eventually led to a complete response for both the primary tumor and all metastases without treatment-related adverse effects. The patient has survived for 26 months after the combined therapy and remains tumor-free currently. This case demonstrates the high inconsistency between immunotherapy response biomarkers and the synergetic anti-tumor effect of immunotherapy and radiotherapy in ICC.

Pu-erh tea is a famous tea worldwide, and identification of the geographical origin of Pu-erh tea can not only protect manufacture’s interests, but also boost consumers’ confidence. However, tree age may also influence the fingerprints of Pu-erh tea. In order to study the effects of the geographical origin and tree age on the interactions of stable isotopes and multi-elements of Pu-erh tea, 53 Pu-erh tea leaves with three different age stages from three different areas in Yunnan were collected in 2023. The δ13C, δ15N values and 25 elements were determined and analyzed. The results showed that δ13C, δ15N, Mg, Mn, Fe, Cu, Zn, Rb, Sr, Y, La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu had significant differences among different geographical origins (p < 0.05). Mn content was significantly influenced by region and tree age interaction. Based on multi-way analysis of variance, principal component analysis and step-wised discriminant analysis, 24 parameters were found to be closely related to the geographical origin rather than tree age, and the geographical origin of Pu-erh tea can be 100.0% discriminated in cross-validation with six parameters (δ13C, δ15N, Mn, Mg, La, and Tb). The study could provide references for the establishment of a database for the traceability of Pu-erh tea, and even the identification of tea sample regions with different tree ages.