Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study.

Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3-36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9-7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.

Distinct oral-associated gastric microbiota and Helicobacter pylori communities for spatial microbial heterogeneity in gastric cancer.

The gastric microbial community plays a fundamental role in gastric cancer (GC), and the two main anatomical subtypes of GC, non-cardia and cardia GC, are associated with different risk factors (Helicobacter pylori for non-cardia GC). To decipher the different microbial spatial communities of GC, we performed a multicenter retrospective analysis to characterize the gastric microbiota in 223 GC patients, including H. pylori-positive or -negative patients, with tumors and paired adjacent normal tissues, using third-generation sequencing. In the independent validation cohort, both dental plaque and GC tumoral tissue samples were collected and sequenced. The prevalence of H. pylori and oral-associated bacteria was verified using fluorescence in situ hybridization (FISH) assays in GC tumoral tissues and matched nontumoral tissues. We found that the vertical distribution of the gastric microbiota, at the upper, middle, and lower third sites of GC, was likely an important factor causing microbial diversity in GC tumor tissues. The oral-associated microbiota cluster, which included Veillonella parvula, Streptococcus oralis, and Prevotella intermedia, was more abundant in the upper third of the GC. However, H. pylori was more abundant in the lower third of the GC and exhibited a significantly high degree of microbial correlation. The oral-associated microbiota module was co-exclusive with H. pylori in the lower third site of the GC tumoral tissue. Importantly, H. pylori-negative GC patients with oral-associated gastric microbiota showed worse overall survival, while the increase in microbial abundance in H. pylori-positive GC patients showed no difference in overall survival. The prevalence of V. parvula in both the dental plaque and GC tissue samples was concordant in the independent validation phase. We showed that the oral-associated species V. parvula and S. oralis were correlated with overall survival. Our study highlights the roles of the oral-associated microbiota in the upper third of the GC. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for H. pylori-negative GCs. IMPORTANCE: Our study highlights the roles of the oral-associated microbiota in the upper third of gastric cancer (GC).We showed that the oral-associated species Veillonella parvula and Streptococcus oralis were correlated with overall survival. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for Helicobacter pylori-negative GCs.

Cationic liposomes as a drug-free system for efficient anticancer therapy by intracytoplasmic delivery of sodium bicarbonate.

Developing the delivery systems with high therapeutic efficacy and low side effects is of great interest and significance for anticancer therapy. Compared to the high cost in synthesizing new chemotherapeutic drugs, exploring the anticancer potentials of existing chemicals is more convenient and efficient. Sodium bicarbonate (BC), a simple inorganic salt, has shown its tumor inhibition capacity via regulating the acidity of tumor microenvironment. However, the effects of intracytoplasmic BC on tumor growth and the potentials of BC to serve as an anticancer agent are still unknown. Herein, we developed a BC-loaded cationic liposome system (BC-CLP) to deliver BC into the cytosol of cancer cells. The in vitro studies showed that the BC-CLP containing 1% BC (w/v) had a size of 112.9 nm and a zeta potential of 19.1 mV, which reduced the viability of the model cancer cells (human oral squamous cell carcinoma HSC-3 cells) to 13.7%. In contrast, the neutral BC-LP caused less than 50% viability reduction. We further found that BC-CLP released BC directly into cytoplasm via membrane fusion pathway rather than endocytosis, leading to the remarkable increase of cytosolic pH, which may contribute to the anticancer effect of BC-CLP. Our findings indicate that BC-CLP is a potential system for high-efficiency cancer therapy without causing drug-related side effects or resistance.

Association Between Young Adult Characteristics and Blood Pressure Trajectories.

BACKGROUND: Blood pressure (BP) trajectories from young adulthood through middle age are associated with cardiovascular risk. We examined the associations of hypertension risk factors with BP trajectories among a large diverse sample. METHODS AND RESULTS: We analyzed data from young adults, aged 18 to 39 years, with untreated BP <140/90 mm Hg at baseline from Kaiser Permanente Southern California (N=355 324). We used latent growth curve models to identify 10-year BP trajectories and to assess the associations between characteristics in young adulthood and BP trajectories. We identified the following 5 distinct systolic BP trajectories, which appeared to be determined mainly by the baseline BP with progressively higher BP at each year: group 1 (lowest BP trajectory, 7.9%), group 2 (26.5%), group 3 (33.0%), group 4 (25.4%), and group 5 (highest BP trajectory, 7.3%). Older age (adjusted odds ratio for 30-39 versus 18-29 years, 1.23 [95% CI, 1.18-1.28]), male sex (13.38 [95% CI, 12.80-13.99]), obesity (body mass index ≥30 versus 18.5-24.9 kg/m2, 14.81 [95% CI, 14.03-15.64]), overweight (body mass index 25-29.9 versus 18.5-24.9 kg/m2, 3.16 [95% CI, 3.00-3.33]), current smoking (1.58 [95% CI, 1.48-1.67]), prediabetes (1.21 [95% CI, 1.13-1.29]), diabetes (1.60 [95% CI, 1.41-1.81]) and high low-density lipoprotein cholesterol (≥160 versus <100 mg/dL, 1.52 [95% CI, 1.37-1.68]) were associated with the highest BP trajectory (group 5) compared with the reference group (group 2). CONCLUSIONS: Traditional hypertension risk factors including smoking, diabetes, and elevated lipids were associated with BP trajectories in young adults, with obesity having the strongest association with the highest BP trajectory group.

Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants.

Metabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public health significance and financial burden. Understanding the connection between point mutations, liver enzymes, and MASLD is important for comprehending drug toxicity in healthy or diseased individuals. Multiple genetic variations have been linked to MASLD susceptibility through genome-wide association studies (GWAS), either increasing MASLD risk or protecting against it, such as PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438. As the impact of genetic variants on the levels of drug-metabolizing cytochrome P450 (CYP) enzymes in human hepatocytes has not been thoroughly investigated, this study aims to describe the analysis of metabolic functions for selected phase I and phase II liver enzymes in human hepatocytes. For this purpose, fresh isolated primary hepatocytes were obtained from healthy liver donors (n = 126), and liquid chromatography-mass spectrometry (LC-MS) was performed. For the cohorts, participants were classified into minor homozygotes and nonminor homozygotes (major homozygotes + heterozygotes) for five gene polymorphisms. For phase I liver enzymes, we found a significant difference in the activity of CYP1A2 in human hepatocytes carrying MBOAT7 (p = 0.011) and of CYP2C8 in human hepatocytes carrying PNPLA3 (p = 0.004). It was also observed that the activity of CYP2C9 was significantly lower in human hepatocytes carrying HSD17B13 (p = 0.001) minor homozygous compared to nonminor homozygous. No significant difference in activity of CYP2E1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, ECOD, FMO, MAO, AO, and CES2 and in any of the phase II liver enzymes between human hepatocytes carrying genetic variants for PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438 were observed. These findings offer a preliminary assessment of the influence of genetic variations on drug-metabolizing cytochrome P450 (CYP) enzymes in healthy human hepatocytes, which may be useful for future drug discovery investigations.

Chitosan and procyanidin composite films with high antioxidant activity and pH responsivity for cheese packaging.

Chitosan-procyanidin composite films (CS-PC films) with different mass ratios were prepared by solution casting method. Their structural, thermal, physical, and antioxidant properties, antibacterial activity and pH responsivity were determined. Compared with CS-control film, CS-PC films exhibited lower solubility and higher tensile strength. The antimicrobial properties against Escherichia coli and Aspergillus niger were improved by 20.0% and 30.4%, respectively. CS-PC films indicated good antioxidant activity through their DPPH and ABTS+ scavenging rates, which were 2.45 times higher than CS-control film. pH responsivity was represented by the outstanding changes in color, which were visible to the naked eye. Food packaging film with high antioxidant activity, bacteriostatic properties and pH responsivity was prepared by CS and PC. Compared with the initial properties of cheese, the characteristics of cheese packaged with CS-PC films were obviously better than those of the control groups.

Drug-free and non-crosslinked chitosan scaffolds with efficient antibacterial activity against both Gram-negative and Gram-positive bacteria.

Treatment of oral pathogens is important for both oral and systemic health. The antimicrobial activity of chitosan (CS)-based scaffolds either loading antibiotics or compositing with other agents are well documented. However, the intrinsic antibacterial activity of CS scaffolds alone has never been reported. Herein, we fabricated the non-crosslinked CS scaffold and investigated its antibacterial activity against typical oral pathogens, Gram-negative Porphyromonas gingivalis and Gram-positive Streptococcus mutans. We found both pathogens were completely killed by 1 mg CS scaffolds at 6 h, due largely to the CS-induced time-dependent bacteria clustering. Interestingly, ß-glycerophosphate crosslinked scaffolds showed no antibacterial activity. In conclusion, the bactericidal activity of CS scaffolds alone is reported for the first time. Together with the biodegradability, physical stability, biocompatibility and great antibacterial activity, the non-crosslinked CS scaffolds may have great potentials not only in treating oral diseases but also in wound healing and tissue engineering.

Diffusion Kurtosis Imaging for Assessing the Therapeutic Response of Transcatheter Arterial Chemoembolization in Hepatocellular Carcinoma.

Objective: This study aimed to evaluate the therapeutic response of hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) with diffusion kurtosis imaging (DKI). Methods: Forty-three patients with fifty-nine hepatic cancer nodules were recruited for this study. All patients were treated by TACE. Magnetic resonance imaging (MRI) and DKI (b=0, 800, 1,500, 2,000mm2/s) were performed before and one month after initiating TACE. Patients were classified as either progressing groups or non-progressing groups. Mean kurtosis (MK), mean diffusion (MD), and apparent diffusion coefficient (ADC) values of the tumor tissue were analyzed. Results: Twenty-three HCCs were classified as progressing groups, and thirty-six HCCs were non-progressing groups. After TACE, the values of MD and ADC in non-progressing groups (1.92±0.36×10-3mm2/s, 1.36±0.23×10-3mm2/s) were greater than progressing groups (1.44±0.32× 10-3mm2/s, 1.10±0.23×10-3mm2/s), however, the MK values in non-progressing groups (0.47±0.12) were lower than progressing groups (0.72±0.14). The MK values of tumor among non-progressing patients decreased one month after TACE (0.47±0.12) relative to the preoperative values (0.71±0.12) (P<0.05). In the non-progressing groups, the MD and ADC values of tumor after TACE (1.92±0.36×10-3mm2/s, 1.36±0.23×10-3mm2/s) became higher than their preoperative values (1.44±0.35×10-3mm2/s, 1.09±0.22×10-3mm2/s) (P<0.05). In the progressing groups, the MK, MD, and ADC values of tumor after TACE remained similar before TACE (P>0.05). The sensitivity, specificity, and AUC of the ROC curve for the assessment of HCC progress after TACE by MK (85.2%, 97.5%, and 0.95, respectively) were greater than by ADC (78.6%, 66.5%, and 0.75, respectively) and MD (76.2%, 64.3%, and 0.71, respectively). Conclusions: DKI for assessing the therapeutic response of TACE in HCC shows great promise. MK is more advantageous in the assessment of HCC progress after TACE.

Comparison of diffusion kurtosis imaging versus diffusion weighted imaging in predicting the recurrence of early stage single nodules of hepatocellular carcinoma treated by radiofrequency ablation.

OBJECTIVE: This study aimed to compare the diffusion kurtosis imaging (DKI) versus diffusion weighted imaging (DWI) in predicting the recurrence of early stage single nodules of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA). MATERIALS AND METHODS: A retrospective analysis of 107 patients with early stage single nodules of HCC was performed, all patients treated by RFA. Recurrence rate of HCC was recorded after a median follow-up of 36 months. During follow-up, the data of magnetic resonance imaging (MRI), DWI and DKI were obtained in multiple time points. The predictive values of DWI and DKI were analyzed using ROC curves. RESULTS: The overall recurrence rate was 66.3% (71/107). The sensitivity, specificity, and AUC for ADC, MD and MK after RFA (78.6, 73.3% and 0.842; 85.7, 83.3% and 0.839; 85.7, 96.7% and 0.956) were higher than before RFA (44.3, 53.3% and 0.560; 51.2, 56.7% and 0.543; 43.6, 67.3% and 0.489). The sensitivity, specificity, and AUC for MK after RFA were 85.7, 96.7%, and 0.956, respectively, which were significantly greater than those of ADC (78.6, 73.3% and 0.842; P < 0.05) and MD (85.7, 83.3% and 0.839). CONCLUSIONS: The prediction efficacy of DKI for the recurrence of early stage single nodules of HCC was better than that of DWI. And, MK was the most sensitive predictor among the DKI.

PICK1 inhibits the E3 ubiquitin ligase activity of Parkin and reduces its neuronal protective effect.

Parkin functions as a multipurpose E3 ubiquitin ligase, and Parkin loss of function is associated with both sporadic and familial Parkinson's disease (PD). We report that the Bin/Amphiphysin/Rvs (BAR) domain of protein interacting with PRKCA1 (PICK1) bound to the really interesting new gene 1 (RING1) domain of Parkin and potently inhibited the E3 ligase activity of Parkin by disrupting its interaction with UbcH7. Parkin translocated to damaged mitochondria and led to their degradation in neurons, whereas PICK1 robustly inhibited this process. PICK1 also impaired the protective function of Parkin against stresses in SH-SY5Y cells and neurons. The protein levels of several Parkin substrates were reduced in young PICK1-knockout mice, and these mice were resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated toxicity. Taken together, the results indicate that PICK1 is a potent inhibitor of Parkin, and the reduction of PICK1 enhances the protective effect of Parkin.

Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity.

Bruton's tyrosine kinase (Btk) is an attractive drug target for treating several B-cell lineage cancers. Ibrutinib is a first-in-class covalent irreversible Btk inhibitor and has demonstrated impressive effects in multiple clinical trials. Herein, we present a series of novel 2,5-diaminopyrimidine covalent irreversible inhibitors of Btk. Compared with ibrutinib, these inhibitors exhibited a different selectivity profile for the analyzed kinases as well as a dual-action mode of inhibition of both Btk activation and catalytic activity, which counteracts a negative regulation loop for Btk. Two compounds from this series, 31 and 38, showed potent antiproliferative activities toward multiple B-cell lymphoma cell lines, including germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) cells. In addition, compound 31 significantly prevented tumor growth in a mouse xenograft model.