Anlotinib Combined With Toripalimab as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Prospective, Multicenter, Phase II Study.

BACKGROUND: For patients with unresectable hepatocellular carcinoma (HCC), the first-line therapeutic options are still relatively limited, and treatment outcomes remain poor. We aimed to assess the efficacy and safety of anlotinib combined with toripalimab as first-line therapy for unresectable HCC. METHODS: In this single-arm, multicenter, phase II study (ALTER-H-003), patients with advanced HCC without previous systemic anticancer therapy were recruited. Eligible patients were given anlotinib (12 mg on days 1-14) combined with toripalimab (240 mg on day 1) in a 3-week cycle. The primary endpoint was the objective response rate (ORR) by immune-related Response Evaluation Criteria in Solid Tumours (irRECIST)/RECIST v1.1 and modified RECIST (mRECIST). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between January 2020 and Jul 2021, 31 eligible patients were treated and included in the full analysis set. At data cutoff (January 10, 2023), the ORR was 29.0% (95% CI: 12.1%-46.0%) by irRECIST/RECIST v1.1, and 32.3% (95% CI: 14.8%-49.7%) by mRECIST criteria, respectively. Confirmed DCR and median DoR by irRECIST/RECIST v1.1 and mRECIST criteria were 77.4 % (95% CI: 61.8%-93.0%) and not reached (range: 3.0-22.5+ months), respectively. Median PFS was 11.0 months (95% CI: 3.4-18.5 months) and median OS was 18.2 months (95% CI: 15.8-20.5 months). Of the 31 patients assessed for adverse events (AEs), the most common grade ≥ 3 treatment-related AEs were hand-foot syndrome (9.7%, 3/31), hypertension (9.7%, 3/31), arthralgia (9.7%, 3/31), abnormal liver function (6.5%, 2/31), and decreased neutrophil counts (6.5%, 2/31). CONCLUSIONS: Anlotinib combined with toripalimab showed promising efficacy and manageable safety in Chinese patients with unresectable HCC in the first-line setting. This combination therapy may offer a potential new therapeutic approach for patients with unresectable HCC.

Enabling Lithium Metal Anode in Nonflammable Phosphate Electrolyte with Electrochemically Induced Chemical Reactions.

Lithium metal anode holds great promises for next-generation battery technologies but is notoriously difficult to work with. The key to solving this challenge is believed to lie in the ability of forming stable solid-electrolyte interphase (SEI) layers. To further address potential safety issues, it is critical to achieve this goal in nonflammable electrolytes. Building upon previous successes in forming stable SEI in conventional carbonate-based electrolytes, here we report that reversible Li stripping/plating could be realized in triethyl phosphate (TEP), a known flame retardant. The critical enabling factor of our approach was the introduction of oxygen, which upon electrochemical reduction induces the initial decomposition of TEP and produces Li3 PO4 and poly-phosphates. Importantly, the reaction was self-limiting, and the resulting material regulated Li plating by limiting dendrite formation. In effect, we obtained a functional SEI on Li metal in a nonflammable electrolyte. When tested in a symmetric Li∥Li cell, more than 300 cycles of stripping/plating were measured at a current density of 0.5 mA cm-2 . Prototypical Li-O2 and Li-ion batteries were also fabricated and tested to further support the effectiveness of this strategy. The mechanism by which the SEI forms was studied by density functional theory (DFT), and the predictions were corroborated by the successful detection of the intermediates and products.

Stable Multimetallic Nanoparticles for Oxygen Electrocatalysis.

Nanostructured catalysts often face an important challenge: poor stability. Many factors contribute to catalytic degradation, including parasitic chemical reactions, phase separation, agglomeration, and dissolution, leading to activity loss especially during long-term catalytic reactions. This challenge is shared by a new family of catalysts, multimetallic nanoparticles, which have emerged owing to their broad tunability and high activity. While significant synthesis-based advances have been made, the stability of these nanostructured catalysts, especially during catalytic reactions, has not been well addressed. In this study, we reveal the critical influence of a synthetic method on the stability of nanostructured catalysts through aprotic oxygen catalysis (Li-O2 battery) demonstrations. In comparison to the conventional wet impregnation (WI) method, we show that the carbothermal shock (CTS) method dramatically improves the overall structural and chemical stability of the catalyst with the same elemental compositions. For multimetallic compositions (4- and 8-elements), the overall stability of the electrocatalysts as well as the battery lifetime can be further improved by incorporating additional noncatalytically active elements into the individual nanoparticles via CTS. The results offer a new synthetic path toward the stabilization of nanostructured catalysts, where additional reaction schemes beyond oxygen electrocatalysis are foreseeable.

A Metal-Organic Framework Thin Film for Selective Mg2+ Transport.

The incompatibility between the anode and the cathode chemistry limits the used of Mg as an anode. This issue may be addressed by separating the anolyte and the catholyte with a membrane that only allows for Mg2+ transport. Mg-MOF-74 thin films were used as the separator for this purpose. It was shown to meet the needs of low-resistance, selective Mg2+ transport. The uniform MOF thin films supported on Au substrate with thicknesses down to ca. 202 nm showed an intrinsic resistance as low as 6.4â€…Ω cm2 , with the normalized room-temperature ionic conductivity of ca. 3.17×10-6  S cm-1 . When synthesized directly onto a porous anodized aluminum oxide (AAO) support, the resulting films were used as a standalone membrane to permit stable, low-overpotential Mg striping and plating for over 100 cycles at a current density of 0.05 mA cm-2 . The film was effective in blocking solvent molecules and counterions from crossing over for extended period of time.

Lichenoid drug eruption caused by imatinib mesylate in a Chinese patient with gastrointestinal stromal tumor.

Imatinib mesylate, the first agent approved for the treatment of unresectable or metastatic gastrointestinal stromal tumor, is a tyrosine kinase inhibitor targeting (KIT) and the platelet-derived growth factor receptor-α and -ß. However, imatinib administration can be accompanied by various adverse events. Here we report a case of Lichenoid drug eruption (LDE) that appeared 24 weeks after commencement of imatinib in a 73-year-old man with gastrointestinal stromal tumor (GIST). The skin lesions were distributed over his face, trunk and limbs, which improved only after discontinuation of imatinib therapy. To the best of our knowledge, this is the first report of imatinib-induced LDE in the Chinese population.

Mechanism of PWAR6 regulating cisplatin drug sensitivity in non-small cell lung cancer through miR-577/PHACTR1.

lncRNA Prader Willi/Angelman Region RNA 6 (PWAR6) is considered to play a protective lncRNA in glioma, but, the role of PWAR6 in the occurrence and cisplatin resistance of non-small cell lung cancer (NSCLC) is elusive. In the study, we aimed to assess the role of PWAR6 in the cisplatin resistance of NSCLC. Based on the oebiotech and TargetScanHuman database, we predicted the interaction between PWAR6, miR-577 and PHACTR1. We then used small interfering RNA (siRNA), miRNA mimics and dual-luciferase reporter assay to explore the regulatory role of PWAR6/miR-577PHACTR1. Based on the online database, miR-577 can interact with PWAR6 and PHACTR1. Soon afterwards, we observed that the expression of PWAR6 and PHACTR1 was increased, while miR-577 expression was decreased in A549/DDP cells. And the cell viability was decreased, while cell apoptosis was increased in A549/DDP cells. What's more, PWAR6 knockdown can promote the expression of miR-577 and inhibit the expression of PHACTR1. PWAR6 knockdown elevated cell proliferation and reduced cell apoptosis of A549/DDP cells. Interestingly, we found that miR-577 can interact with PHACTR1 to regulate the proliferation and apoptosis of A549/DDP cells. To conclude, we speculated that PWAR6 knockdown elevated cell proliferation and reduced cell apoptosis of A549/DDP cells via miR-577/PHACTR1, providing the theoretical basis for the clinical treatment of NSCLC patients.

Integrative pan-cancer analysis reveals the importance of PAQR family in lung cancer.

BACKGROUND: The progestin and adipoQ receptors (PAQRs) family contains 11 genes involved in the regulation of metabolism and cancer development. However, a comprehensive understanding of the role of PAQRs in cancer remains largely scarce, and the associations between their expression levels and immune signatures also need to be researched. METHODS: Here, we applied pan-cancer analysis to explore the associations between PAQRs expression and survival, tumor microenvironment (TME), and drug sensitivity from the UCSC Xena and CellMiner databases. Besides, we further studied the expression, survival and somatic mutations of PAQRs in lung cancer (LC) from TCGA database. RESULTS: The results showed that PAQRs had significant heterogeneity with some upregulation and some downregulation in most tumors. Specifically, compared with PAQR3/5/6/9 and MMD2, ADIPOR1/2, PAQR4/7/8 and MMD had higher levels of average expression in all tumor types. PAQRs expression was greatly correlated with survival, immune subtypes, TME, and drug sensitivity. Furthermore, this research concentrated on analyzing the relationship of PAQRs expression with LC prognosis, and proved that ADIPOR2, PAQR4/9 and MMD were independent prognostic factors for LC patients. Finally, based on somatic mutation data, the genetic mutations in LC patients were majorly missense mutations, and TP53 and TTN had the top two highest mutation frequencies. CONCLUSION: Collectively, PAQRs may serve as robust biomarkers to predict the prognosis and guide immunotherapy of tumors, especially LC, which enables novel ways for improving cancer treatment.

Association between the degree of fibrosis in fibrotic focus and the unfavorable clinicopathological prognostic features of breast cancer.

OBJECTIVE: To explore the association between the degree of fibrosis in fibrotic focus (FF) and the unfavorable clinicopathological prognostic features of breast cancer. METHODS: A total of 169 cases of breast invasive ductal carcinoma (IDC) were included in the study. Hematoxylin and eosin (H&E) staining was performed in the primary lesion of breast IDC and the degree of fibrosis in tumor-stromal FF was assessed. The association between the degree of fibrosis in FF and the well-known clinicopathologic features of breast cancer was investigated and the influence of the degree of fibrosis in FF on the survival was analyzed. RESULTS: Tumor size >2 cm (P = 0.023), vascular invasion (P = 0.011), lymphatic vessel invasion (P < 0.001) and HER-2+ (P = 0.032) were positively correlated with the degree of fibrosis in FF in breast IDC. The result of multivariate analysis showed that lymphatic vessel invasion was the only independent correlation factor of high fibrosis in FF in breast IDC (OR = 3.82, 95% CI[1.13 ∼ 12.82], P = 0.031). The Nottingham prognostic index (NPI) of high fibrosis in FF was significantly higher than that of mild and moderate fibrosis in FF in the no vascular infiltration subgroup, the no nerve infiltration subgroup, and the Luminal A subgroup (P = 0.014, 0.039, and 0.018; respectively). CONCLUSIONS: The high fibrosis in FF is closely associated with the strong invasiveness and the high malignancy of breast IDC. The degree of fibrosis in FF might be considered as a very practical and meaningful pathological feature of breast cancer.

Enabling rechargeable non-aqueous Mg-O2 battery operations with dual redox mediators.

Dual redox mediators (RMs) were introduced for Mg-O2 batteries. 1,4-Benzoquinone (BQ) facilitates the discharge with an overpotential reduction of 0.3 V. 5,10,15,20-Tetraphenyl-21H,23H-porphine cobalt(ii) (Co(ii)TPP) facilitates the recharge with an overpotential decrease of up to 0.3 V. Importantly, the two redox mediators are compatible in the same DMSO-based electrolyte.

An analysis of reentrant loops.

Reentrant loops are an important structural motif in alpha-helical transmembrane proteins. A reentrant loop is a structural motif that goes only halfway through the membrane and then turns back to the side from which it originates. The question of what causes the reentrant loops to form such a unique topology is still unanswered. In this study, we try to answer this question by analyzing the hydrophobicity distribution on the amino acid sequences of the reentrant loops. Our results show that reentrant loops have very low hydrophobicity around the deepest point buried in the membrane and relative high hydrophobicity close to the membrane surfaces. We speculate that this hydrophobicity distribution is a major force that stabilizes the unique reentrant loop structure. Our results also show that this hydrophobicity distribution results in special patterns on protein sequences, which can be captured using profile hidden Markov models (HMMs). The resulting profile HMMs can detect reentrant loops on protein sequences with high sensitivity and perfect specificity.