Immune checkpoint inhibitors in cancer: the increased risk of atherosclerotic cardiovascular disease events and progression of coronary artery calcium.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have contributed to a significant advancement in the treatment of cancer, leading to improved clinical outcomes in many individuals with advanced disease. Both preclinical and clinical investigations have shown that ICIs are associated with atherosclerosis and other cardiovascular events; however, the exact mechanism underlying this relationship has not been clarified. METHODS: Patients diagnosed with stages III or IV non-small cell lung cancer (NSCLC) at the Wuhan Union Hospital from March 1, 2020, to April 30, 2022, were included in this retrospective study. Coronary artery calcium (CAC) volume and score were assessed in a subset of patients during non-ECG-gated chest CT scans at baseline and 3, 6, and 12 months after treatment. Propensity score matching (PSM) was performed in a 1:1 ratio to balance the baseline characteristics between the two groups. RESULTS: Overall, 1458 patients (487 with ICI therapy and 971 without ICI therapy) were enrolled in this cardiovascular cohort study. After PSM, 446 patients were included in each group. During the entire period of follow-up (median follow-up 23.1 months), 24 atherosclerotic cardiovascular disease (ASCVD) events (4.9%) occurred in the ICI group, and 14 ASCVD events (1.4%) in the non-ICI group, before PSM; 24 ASCVD events (5.4%) occurred in the ICI group and 5 ASCVD events (1.1%) in the non-ICI group after PSM. The CAC imaging study group comprised 113 patients with ICI therapy and 133 patients without ICI therapy. After PSM, each group consisted of 75 patients. In the ICI group, the CAC volume/score increased from 93.4 mm3/96.9 (baseline) to 125.1 mm3/132.8 (at 12 months). In the non-ICI group, the CAC volume/score was increased from 70.1 mm3/68.8 (baseline) to 84.4 mm3/87.9 (at 12 months). After PSM, the CAC volume/score was increased from 85.1 mm3/76.4 (baseline) to 111.8 mm3/121.1 (12 months) in the ICI group and was increased from 74.9 mm3/76.8 (baseline) to 109.3 mm3/98.7 (12 months) in the non-ICI group. Both cardiovascular events and CAC progression were increased after the initiation of ICIs. CONCLUSIONS: Treatment with ICIs was associated with a higher rate of ASCVD events and a noticeable increase in CAC progression.

Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides.

Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.

Heart Rate Response Predicts 6-Minutes Walking Distance in Pulmonary Arterial Hypertension.

Because the 6-minute walking test (6MWT) is a self-paced submaximal test, the 6-minute walking distance (6MWD) is substantially influenced by individual effort level and physical condition, which is difficult to quantify. We aimed to explore the optimal indicator reflecting the perceived effort level during 6MWT. We prospectively enrolled 76 patients with pulmonary arterial hypertension and 152 healthy participants; they performed 2 6MWTs at 2 different speeds: (1) at leisurely speed, as performed in daily life without extra effort (leisure 6MWT) and (2) an increased walking speed, walking as the guideline indicated (standard 6MWT). The factors associated with 6MWD during standard 6MWT were investigated using a multiple linear regression analysis. The heart rate (HR) and Borg score increased and oxygen saturation (SpO2) decreased after walking in 2 6MWTs in both groups (all p <0.001). The ratio of difference in HR before and after each test (ΔHR) to HR before walking (HRat rest) and the difference in SpO2 (ΔSpO2) and Borg (ΔBorg) before and after each test were all significantly higher in both groups after standard 6MWT than after leisure 6MWT (all p <0.001). Multiple linear regression analysis revealed that ΔHR/HRat rest was an independent predictor of 6MWD during standard 6MWT in both groups (both p <0.001, adjusted R2 = 0.737 and 0.49, respectively). 6MWD and ΔHR/HRat rest were significantly lower in patients than in healthy participants (both p <0.001) and in patients with cardiac functional class III than in patients with class I/II (both p <0.001). In conclusion, ΔHR/HRat rest is a good reflector of combined physical and effort factors. HR response should be incorporated into 6MWD to better assess a participant's exercise capacity.

The effect of a body shape index (ABSI) and its interaction with low estimated glomerular filtration rate (eGFR) on osteoporosis in elderly Chinese.

BACKGROUND: Both obesity and chronic kidney disease (CKD) contribute to osteoporosis risk, but the effect of a newly developed index (e.g., a body shape index, ABSI) of central obesity and its interaction with low estimated glomerular filtration rate (eGFR) on osteoporosis remains unknown. METHODS: A total of 2534 Chinese individuals were enrolled in our ongoing cohort study: Osteoporosis Preventive Project. ABSI and eGFR were calculated as obesity-related indexes and renal function markers, respectively. A logistic regression model was used to estimate the association between osteoporosis and related clinical parameters (e.g., ABSI, eGFR), and to assess the additive and multiplicative interactions between risk factors and osteoporosis. Relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (SI) were calculated to assess the additive interaction. RESULTS: High ABSI was significantly associated with an increased risk of osteoporosis in participants compared with the lowest quartile of ABSI in both crude and adjusted models. Individuals in the lower quartiles of eGFR had a significantly increased risk of osteoporosis compared with those in the highest quartiles in crude models. After adding age and other variables in the model, the association was abolished. In addition, after adjusting for variables, high ABSI with low eGFR (RERI: 0.45, 95% CI: 0.15-0.75; AP: 0.39, 95% CI: 0.17-0.60) still displayed a noticeable interaction on the risk of osteoporosis. The multiplicative interactive effect between high ABSI with low eGFR on osteoporosis was statistically significant in the multivariable-adjusted model (P < 0.05). CONCLUSION: Our study indicated that higher ABSI increases the risk of osteoporosis independently and synergistically with low eGFR in Chinese elderly adults. The findings increase our understanding of the interactions of osteoporosis risk factors and may help provide potential interventions for osteoporosis.

Body Surface Area (BSA) is a Better Osteoporosis Associated Anthropometric Parameter Than Other Anthropometric Parameters in Elderly Population.

Body surface area (BSA) is widely used for adjusting drug dose, while few studies have yet systematically evaluated its association with osteoporosis and compared its advantage with other anthropometric parameters in osteoporotic risk prediction. A total of 10,021 Chinese individuals aged over 65 years were enrolled in our study. Bone mineral density (BMD) was measured, and demographic information was also collected. Pearson correlation analysis, receiver operating characteristic (ROC) curves and predictive analysis were performed to assess the clinical practice of BSA for osteoporosis. BSA had the strongest correlation with BMD (0.544, p < 0.001) compared with conventional anthropometric indices. Besides, BSA had the highest power in osteoporosis prediction, with an area under the curve (AUC) reaching 0.81. After incorporating BSA into the osteoporosis risk prediction model, the AUC improved from 0.82 to 0.83 (p < 0.01). We found BSA provided additional diagnostic value beyond conventional anthropometric information with continuous and category NRIs were 30.40% (p < 0.01) and 3.29% (p < 0.01), respectively, and the IDI was 1.85% (p < 0.01). BSA was positively associated with osteoporosis and showed superior discriminative ability for osteoporosis risk prediction compared with other anthropometric parameters in the Chinese elderly population.

Optimization of flask culture medium and conditions for hyaluronic acid production by a streptococcus equisimilis mutant nc2168

A mutant designated NC2168, which was selected from wild-type Streptococcus equisimilis CVCC55116by ultraviolet ray combined with60Co-γ ray treatment and does not produce streptolysin, was employed to produce hyaluronic acid (HA). In order to increase the output of HA in a flask, the culture medium and conditions for NC2168 were optimized in this study. The influence of culture medium ingredients including carbon sources, nitrogen sources and metal ions on HA production was evaluated using factional factorial design. The mathematical model, which represented the effect of each medium component and their interaction on the yield of HA, was established by the quadratic rotary combination design and response surface method. The model estimated that, a maximal yield of HA could be obtained when the concentrations of yeast extract, peptone, glucose, and MgSO4 were set at 3 g/100 mL, 2 g/100 mL, 0.5 g/100 mL and 0.15 g/100 mL, respectively. Compared with the values obtained by other runs in the experimental design, the optimized medium resulted in a remarkable increase in the output of HA and the maximum of the predicted HA production was 174.76 mg/L. The model developed was accurate and reliable for predicting the production of HA by NC2168.Cultivation conditions were optimized by an orthogonal experimental design and the optimal conditions were as follows: temperature 33ºC, pH 7.8, agitation speed 200 rpm, medium volume 20 mL.

Optimization of flask culture medium and conditions for hyaluronic acid production by a Streptococcus equisimilis mutant nc2168.

A mutant designated NC2168, which was selected from wild-type Streptococcus equisimilis CVCC55116 by ultraviolet ray combined with(60)Co-γ ray treatment and does not produce streptolysin, was employed to produce hyaluronic acid (HA). In order to increase the output of HA in a flask, the culture medium and conditions for NC2168 were optimized in this study. The influence of culture medium ingredients including carbon sources, nitrogen sources and metal ions on HA production was evaluated using factional factorial design. The mathematical model, which represented the effect of each medium component and their interaction on the yield of HA, was established by the quadratic rotary combination design and response surface method. The model estimated that, a maximal yield of HA could be obtained when the concentrations of yeast extract, peptone, glucose, and MgSO4 were set at 3 g/100 mL, 2 g/100 mL, 0.5 g/100 mL and 0.15 g/100 mL, respectively. Compared with the values obtained by other runs in the experimental design, the optimized medium resulted in a remarkable increase in the output of HA and the maximum of the predicted HA production was 174.76 mg/L. The model developed was accurate and reliable for predicting the production of HA by NC2168.Cultivation conditions were optimized by an orthogonal experimental design and the optimal conditions were as follows: temperature 33°C, pH 7.8, agitation speed 200 rpm, medium volume 20 mL.

[Clinical study of deoxyribonucleotidum for adjuvant treatment of pulmonary tuberculosis with hepatic lesion].

OBJECTIVE: To evaluate of therapeutic efficacy of deoxyribouncleotidum on pulmonary tuberculosis. METHODS: Eighty patients with pulmonary tuberculosis sustaining hepatic lesion after treatment with antituberculosis drugs were randomized into therapeutic group and control group. Patients in the control group received regular treatment and those in the therapeutic group had additional deoxyribouncleotidum injection. RESULTS: ALT, AST, ALP and TBIL levels were significantly higher in the therapeutic group than in the control group 4 weeks after treatment. IgG, IgA, IgM levels, and CD3(+) and CD8(+) lymphocytes were significantly increased in the therapeutic group after treatment (P<0.05). CONCLUSION: deoxyribouncleotidum can improve hepatic function and immunity in patients with pulmonary tuberculosis.