Landscape and prognostic values of lymphocytes in patients with hepatocellular carcinoma undergoing transarterial embolization.

Transarterial embolization (TACE), the first-line treatment for hepatocellular carcinoma (HCC), does not always lead to promising outcomes in all patients. A better understanding of how the immune lymphocytes changes after TACE might be the key to improve the efficacy of TACE. However, there are few studies evaluating immune lymphocytes in TACE patients. Therefore, we aimed to evaluate the short- and long-term effects of TACE on lymphocyte subsets in patients with HCC to identify those that predict TACE prognosis. Peripheral blood samples were collected from 44 HCC patients at the following time points: one day before the initial TACE, three days after the initial TACE, and one month after the initial TACE and subjected to peripheral blood mononuclear cell isolation and flow cytometry. Dynamic changes in 75 lymphocyte subsets were recorded and their absolute counts were calculated. Tumor assessments were made every 4-6 weeks via computed tomography or magnetic resonance imaging. Our results revealed that almost all lymphocyte subsets fluctuated three days after TACE, but only Tfh and B cells decreased one month after TACE. Univariate and multivariate Cox regression showed that high levels of Th2 and conventional killer Vδ2 cells were associated with longer progressive-free survival (PFS) after TACE. Longer overall survival (OS) after TACE was associated with high levels of Th17 and viral infection-specific Vδ1 cells, and low levels of immature NK cells. In conclusion, TACE has a dynamic influence on the status of lymphocytes. Accordingly, several lymphocyte subsets can be used as prognostic markers for TACE.

Cost-effectiveness analysis of fruquintinib in Chinese patients with refractory metastatic colorectal cancer.

BACKGROUND: Colorectal cancer is a significant health concern worldwide, with metastatic CRC (mCRC) presenting a particularly challenging prognosis. The FRESCO-2 trial highlighted the potential of fruquintinib in heavily pretreated mCRC patients. AIM: Given the recent changes in drug pricing in China and the evolving mCRC treatments, this study aimed to evaluate the cost-effectiveness of fruquintinib in the context of current Chinese healthcare standards. METHOD: This study utilized data from the FRESCO-2 trial, incorporating a partitioned-survival model to simulate three health states: Progression-Free Survival, Progressive Disease, and death. Costs and utility values were derived from published literature and the FRESCO-2 trial. Sensitivity analyses were conducted to assess the robustness of the base-case result and to understand the impact of various parameters on the ICER. RESULTS: The base-case analysis revealed a total cost of $11,089.05 for the fruquintinib group and $5,374.48 for the placebo group. The overall QALYs were higher in the fruquintinib group (0.61 QALYs) compared to the placebo group (0.43 QALYs). The ICER was calculated to be $31,747.67 per QALY. Sensitivity analyses identified the utility of progression-free survival, the cost of fruquintinib, and the costs of best supportive care as significant determinants of ICER. CONCLUSION: Fruquintinib emerges as a promising therapeutic option for refractory mCRC. However, its cost-effectiveness depends on selected willingness-to-pay (WTP) threshold. While the drug's ICER surpasses the WTP based on China's 2022 GDP per capita, it remains below the threshold set at three times the national GDP.

Multi-Mode Damage and Fracture Mechanisms of Thin-Walled Tubular Parts with Cross Inner Ribs Manufactured via Flow Forming.

In order to study the multi-mode damage and fracture mechanisms of thin-walled tubular parts with cross inner ribs (longitudinal and transverse inner ribs, LTIRs), the Gurson-Tvergaard-Needleman (GTN) model was modified with a newly proposed stress state function. Thus, tension damage and shear damage were unified by the new stress state function, which was asymmetric with respect to stress triaxiality. Tension damage dominated the modification, which coupled with the shear damage variable, ensured the optimal prediction of fractures of thin-walled tubular parts with LTIRs by the modified GTN model. This included fractures occurring at the non-rib zone (NRZ), the longitudinal rib (LIR) and the interface between the transverse rib (TIR) and the NRZ. Among them, the stripping of material from the outer surface of the tubular part was mainly caused by the shearing of built-up material in front of the rollers under a large wall thickness reduction (ΔT). Shear and tension deformation were the causes of fractures occurring at the NRZ, while axial tension under a large TIR interval (l) mainly resulted in fractures on LIRs. Fractures at the interface between the TIR and NRZ were due to the shearing applied by rib grooves and radial tension during the formation of ribs. This study can provide guidance for the manufacturing of high-performance aluminum alloy thin-walled tubular components with complex inner ribs.

A GSH-resistant FK228 analogue containing a stable disulfide bond.

FK228 is a potent natural pan HDAC inhibitor approved by the FDA for the treatment of cutaneous T-cell lymphoma as well as peripheral T-cell lymphoma. It is generally believed that the mechanism of FK228 acting on HDACs is by reducing its disulfide bond after entering the cell, and the dithiol group may chelate with Zn2+ and form a weak reversible covalent bond with cysteine in the catalytic pocket of HDACs, therefore inhibiting the activity of HDACs. However, due to the weak stability of the disulfide bond in FK228, it has been difficult to obtain direct evidence for the above conjecture. Thus, improving the stability of the FK228 disulfide bond will help to explore the exact mechanism of FK228. In this study, based on the stability and target-induced covalent properties of the Cysteine-Penicillamine (Cys-Pen) disulfide bond reported previously, the Pen was introduced into the modification of FK228. Specifically, the d-Cys in FK228 was replaced by d-Pen, the total synthetic pathway was optimized, and the novel synthetic FK228 analogue (FK-P) stability was verified. FK-P can also be used as a new drug molecule in the future to participate in the research of related biological mechanisms or the treatment of diseases.

Development of Lysine Crotonyl-Mimic Probe to Covalently Identify H3K27Cr Interacting Proteins.

Histone lysine crotonylation (Kcr) is one newly discovered acylation modification and regulates numerous pathophysiological processes. The binding affinity between Kcr and its interacting proteins is generally weak, which makes it difficult to effectively identify Kcr-interacting partners. Changing the amide of crotonyl to an ester increased reactivity with proximal cysteines and retained specificity for Kcr antibody. The probe "H3g27Cr" was designed by incorporating the ester functionality into a H3K27 peptide. Using this probe, multiple Kcr-interacting partners including STAT3 were successfully identified, and this has not been reported previously. Further experiments suggested that STAT3 possibly could form complexes with Histone deacetylase HDACs to downregulate the acetylation and crotonylation of Histone H3K27. Our unique design provided intriguing tools to further explore Kcr-interacting proteins and elucidate their working mechanisms.

Cost-effectiveness analysis of trastuzumab deruxtecan in patients with HER2-low advanced breast cancer based on DESTINY-Breast04.

Background and purpose: Breast cancer is a rapidly raising healthcare problem worldwide. DESTINY-Breast04 demonstrated that trastuzumab deruxtecan (T-Dxd) had a survival advantage comparing to the physician's choice of chemotherapy for patients with HER2-low metastatic breast cancer. But at the same time, this expensive novel treatment also brought an economic burden. This study assessed the cost-effectiveness of T-Dxd based on results of DESTINY-Breast04 from the perspective of Chinese healthcare system. Materials and methods: A three-state partitioned-survival model [progression-free survival (PFS), progressive disease (PD) and death] based on data from DESTINY-Breast04 and Chinese healthcare system was used to estimate the incremental cost-effectiveness ratio (ICER) of T-Dxd vs. the physician's choice of chemotherapy for HER2-low metastatic breast cancer. Costs, quality-adjusted life-years (QALYs) and the ICER in terms of 2022 US$ per QALY gained were calculated for both hormone receptor-positive cohort and all patients. One-way and probabilistic sensitivity analyses were performed to assess the model robustness. Results: Compared with the physician's choice of chemotherapy, T-Dxd increased costs by $104,168.30, while gaining 0.31 QALYs, resulting in an ICER of $336,026.77 per QALY in all patients. The costs of T-Dxd and the utility of PFS were the crucial factors in determining the ICER. In the hormone receptor-positive cohort, the ICER was lower than that in all patients, with the ICER of $274,905.72 per QALY. The ICER was much higher than the commonly accepted willingness-to-pay threshold ($357,96.83 per QALY). Conclusion: T-Dxd as second- or subsequent-line treatment is not a cost-effective treatment option for HER2-low metastatic breast cancer from the perspective of the Chinese healthcare system.

[Influence of the Classification of Municipal Solid Wastes on the Reduction of Greenhouse Gas Emissions: A Case Study of Qingdao City, China].

The municipal solid waste (MSW) sector is an important source of greenhouse gas (GHG) emissions. MSW classification can achieve waste reduction and improve resource utilization. However, few studies have investigated the effects of MSW classification on GHG emission reduction. Therefore, the GHG emissions under different MSW disposal modes before and after classification were studied based on the life cycle assessment method in the four districts of Qingdao City. The results showed that MSW classification could significantly reduce the GHG emissions during the whole MSW treatment process. The net carbon emissions(in CO2/MSW)during the whole process of waste treatment for mode 1 (mixed collection+landfill), mode 2 (mixed collection+incineration), mode 3 (waste classification+anaerobic digestion of food waste and other incineration), and mode 4 (waste classification+anaerobic digestion of food waste, recycling of recyclable waste, and other incineration) were 686.39, -130.12, -61.88, and -230.17 kg·t-1, respectively. Improving the classification efficiency of food waste had no significant impact on carbon emissions. The reduction in carbon emissions increased linearly with the improvement of waste recycling efficiency. For every 10% increase in the recovery efficiency of recyclable waste, the net carbon emission decreased by 26.6%(16.5 kg·t-1). Appropriate separation of food waste, improving the recycling efficiency of recyclable waste, and reducing the leakage rate of biogas from anaerobic digestion are feasible strategies to reduce carbon emissions from MSW disposal units through the classification of MSW.

Immunotherapy combined with antiangiogenic agents in patients with advanced malignant pleural mesothelioma: A case report.

BACKGROUND: Malignant pleural mesothelioma has limited therapeutic options and a poor outcome. Antiangiogenic agents might increase the efficacy of immunotherapy as second-line treatment of advanced-stage malignancies. CASE SUMMARY: A patient with stage IIIB pleural mesothelioma received second-line treatment with a combination of pembrolizumab, bevacizumab and chemotherapy following standard chemotherapy under the guidance of second-generation sequencing. He achieved a partial response after four cycles of treatment with progression-free survival of 5 mo. Pembrolizumab was suspended due to grade 2 immunerelated pneumonia, which was resolved by oral glucocorticoids. However, disease progression was observed after immunotherapy rechallenge and anlotinib therapy. The patient had disease progression, multiorgan dysfuntion and died suddenly in October 2019. CONCLUSION: The combination of immune checkpoint inhibitor, anti-angiogenic agents and chemotherapy showed effective response for advanced pleural mesothelioma, but with adverse reactions.

Efficacy and Safety of Bevacizumab Biosimilars Compared With Reference Biologics in Advanced Non-small Cell Lung Cancer or Metastatic Colorectal Cancer Patients: A Network Meta-Analysis.

Background: Bevacizumab biosimilars are slowly making their way into cancer treatment, but the data on their efficacy and safety in cancer patients are still poor. We systematically summarized the current evidence for the efficacy and safety of bevacizumab biosimilars in patients with advanced non-small cell lung cancer (NSCLC) or metastatic colorectal cancer (CRC). Methods: This review searched CNKI, VIP, PubMed, Medline (Ovid), Embase, and Cochrane Library (Ovid) for randomized controlled trials of bevacizumab biosimilars treated in adults with advanced NSCLC or metastatic CRC. A pairwise meta-analysis and a Bayesian network meta-analysis based on the random-effect model were performed to summarize the evidence. We rated the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation framework. Results: Ten eligible trials with a total of 5526 patients were included. Seven trials (n = 4581) were for the NSCLC population, while three trials (n = 945) were for patients with CRC. According to the pairwise meta-analysis, the efficacy (objective response rate: risk ratio (RR) 0.98 [0.92-1.04], p = 0.45; progression-free survival: hazard ratio (HR) 1.01 [0.92-1.10], p = 0.85; and overall survival: HR 1.06 [0.94-1.19], p = 0.35) and safety (incidence of grade 3-5 adverse events: odds ratio (OR) 1.03 [0.91-1.16], p = 0.65) of bevacizumab biosimilars performed no significant difference with reference biologics in patients with NSCLC as well as metastatic CRC patients (objective response rate: RR 0.97 [0.87-1.09], p = 0.60; overall survival: HR 0.94 [0.70-1.25], p = 0.66; incidence of grade 3-5 adverse events: OR 0.78 [0.59-1.02], p = 0.73). Network estimates displayed 7 types of bevacizumab biosimilars in the medication regime of NSCLC patients who had no significant difference among each other in terms of efficacy and safety. The certainty of the evidence was assessed as low to moderate. Three types of biosimilars were found to be clinically equivalent to each other in the patients with CRC, which were evaluated with very low to moderate certainty. Conclusion: In patients with advanced NSCLC or metastatic CRC, the efficacy and safety of bevacizumab biosimilars were found to be comparable with those of reference biologics and each other.

[Clinical features of intestinal polyps and risk factors for secondary intussusception in children: an analysis of 2 669 cases]. / 2 669ä¾‹å„¿ç«¥è‚ æ¯è‚‰çš„ä¸´åºŠç‰¹å¾åŠç»§å‘è‚ å¥—å çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To study the clinical features of intestinal polyps and the risk factors for secondary intussusception in children. METHODS: A retrospective analysis was performed for the medical data of 2 669 children with intestinal polyps. According to the presence or absence of secondary intussusception, they were divided into two groups: intussusception (n=346) and non-intussusception (n=2 323). Related medical data were compared between the two groups. The multivariate logistic regression analysis was used to identify the risk factors for secondary intussusception. RESULTS: Among the children with intestinal polyps, 62.42% were preschool children, and the male/female ratio was 2.08∶1; 92.66% had hematochezia as disease onset, and 94.34% had left colonic polyps and rectal polyps. There were 346 cases of secondary intussusception, with an incidence rate of 12.96% (346/2 669). Large polyps (OR=1.644, P<0.001), multiple polyps (≥2) (OR=6.034, P<0.001), and lobulated polyps (OR=93.801, P<0.001) were the risk factors for secondary intussusception. CONCLUSIONS: Intestinal polyps in children often occur in preschool age, mostly in boys, and most of the children have hematochezia as disease onset, with the predilection sites of the left colon and the rectum. Larger polyps, multiple polyps, and lobulated polyps may increase the risk of secondary intussusception, and endoscopic intervention is needed as early as possible to improve prognosis.

Cost-Effectiveness Analysis of Pembrolizumab in Patients With Advanced Esophageal Cancer Based on the KEYNOTE-181 Study.

Background and Purpose: The KEYNOTE-181 study demonstrated that pembrolizumab for advanced or metastatic esophageal cancer in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10 had a survival advantage and better tolerability than chemotherapy. However, at the same time, pembrolizumab places an economic burden on patients. This study assessed the cost-effectiveness of pembrolizumab based on the KEYNOTE181 study. Materials and Methods: A three-state Markov model [progression-free survival (PFS), progressive disease (PD), and death] based on data from the KEYNOTE-181 study was used to estimate the incremental cost-effectiveness ratio (ICER) of pembrolizumab versus chemotherapy for advanced or metastatic esophageal cancer. The model evaluates the outcomes from the Chinese society's perspective. Costs, quality-adjusted life-years (QALYs), and the ICER in terms of 2021 US$ per QALY gained, were calculated. one-way and probabilistic sensitivity analyses were performed to evaluate the model robustness. Results: Compared with chemotherapy, pembrolizumab increased costs by $37,201.68, while gaining 0.23 QALYs, resulting in an ICER of $163,165.26 per QALY in patients with PD-L1 CPS ≥ 10. The ICER is $202,708.62 per QALY and $163,643.19 per QALY in the total population and patients with esophageal squamous cell carcinoma, respectively. The ICER was much higher than the commonly accepted willingness-to-pay threshold ($11,105.8 per QALY). One-way and sensitivity analyses showed that the costs of pembrolizumab and the utility of PD were the crucial factors in determining the ICER, and probabilistic sensitivity analyses demonstrated pembrolizumab is unlikely to be cost-effective at a willingness-to-pay threshold of $11,105.8 per QALY. The result was robust across sensitivity analyses. Conclusion: Pembrolizumab is not a cost-effective treatment option for the second-line treatment of esophageal cancer from the perspective of Chinese society.

PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma.

OBJECTIVE: Patients with increased PD-L1+ host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1+ host cells in hepatocellular carcinoma (HCC). DESIGN: A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1+ cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies. RESULTS: We demonstrate that PD-L1+ host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRhighCD86high glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2+ glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties. CONCLUSIONS: Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.

Chemo-Selective Cys-Pen Disulfide for Proximity-Induced Cysteine Cross-Linking.

Disulfide-rich architectures are valuable pharmacological tools or therapeutics. Besides, a ligand-induced conjugate strategy offers potential advantages in potency, selectivity, and duration of action for novel covalent drugs. Combining the plentiful disulfide-rich architecture library and ligand-induced conjugate via thiol-disulfide interchange would supply great benefits for developing site specific covalent inhibitors. Cysteine-cysteine (Cys-Cys) disulfide bonds are intrinsically unstable in endogenous reductive environment, while cysteine-penicillamine (Cys-Pen) disulfide bonds show satisfactory stability. We envisioned the Cys-Pen disulfide as a potential ligand-induced covalent bonding warhead, and this disulfide could reconstruct with the protein cysteine in the vicinity of the peptide binding site to form a new disulfide. To evaluate our design, protein PLCγ1-c src homology 2 domain and RGS3-PDZ domain were tested as models. Both proteins were successfully modified by Cys-Pen disulfide and formed new disulfides between proteins and peptides. The new disulfide was then analyzed to confirm it was a newly formed disulfide bond between Pen of the ligand and a protein Cys near the ligand binding site. HDAC4 was then chosen as a model by utilizing its "CXXC" domain near its catalytic pocket. The designed Cys-Pen cyclic peptide inhibitor of HDAC4 showed satisfactory selectivity and inhibitory effect.

The analgesic effects of ulinastatin either as a single agent or in combination with sufentanil: A novel therapeutic potential for postoperative pain.

Ulinastatin is a broad-spectrum protease inhibitor widely used for the treatment of various inflammation-related diseases owing to its recognized excellent anti-inflammatory and cytoprotective properties. However, whether ulinastatin can relieve postoperative pain remains unclear. In this study, we evaluated the analgesic effects of ulinastatin administered either as a single agent or in combination with sufentanil in a validated preclinical rat model of postoperative pain induced by plantar incision. We found that incisional surgery on the hind paw of these rats induced sustained ipsilateral mechanical pain hypersensitivity that lasted for at least 10 days. A single intraperitoneal (i.p.) injection of ulinastatin prevented the development and reversed the maintenance of incision-induced mechanical pain hypersensitivity in a dose-dependent manner. However, ulinastatin had no effect on the baseline nociceptive threshold. Moreover, repeated i.p. injections of ulinastatin persistently attenuated incision-induced mechanical pain hypersensitivity and promoted recovery from the surgery. The rats did not develop any analgesic tolerance over the course of repeated injections of ulinastatin. A single i.p. injection of ulinastatin was also sufficient to inhibit the initiation and maintenance of incision-induced hyperalgesic priming when the rats were subsequently challenged with an ipsilateral intraplantar prostaglandin E2 injection. Furthermore, the combined administration of ulinastatin and sufentanil significantly enhanced the analgesic effect of sufentanil on postoperative pain, which involved mechanisms other than a direct influence on opioid receptors. These findings demonstrated that ulinastatin had a significant analgesic effect on postoperative pain and might be a novel pharmacotherapeutic agent for managing postoperative pain either alone or as an adjuvant.

Nano-enabled coordination platform of bismuth nitrate and cisplatin prodrug potentiates cancer chemoradiotherapy via DNA damage enhancement.

The combination of chemotherapy and radiotherapy (chemoradiotherapy) is a promising strategy, extensively studied and applied clinically. Meanwhile, radiosensitizers play an important role in improving clinical radiotherapy therapeutic efficacy. There are still some disadvantages in practical applications, because radiosensitizers and drugs are difficult to deliver spatio-temporally to tumor sites and work simultaneously with low efficiency for DNA damage and repair inhibition, leading to an inferior synergistic effect. Herein, a suitable radiosensitizer of nano-enabled coordination platform (NP@PVP) with bismuth nitrate and cisplatin prodrug is developed by a simple synthetic route to improve the effectiveness of chemo-radiation synergistic therapy. When NP@PVP is internalized by a tumor cell, the bismuth in NP@PVP can sensitize radiation therapy (RT) by increasing the amount of reactive oxygen species generation to enhance DNA damage after X-ray radiation; meanwhile, the cisplatin in NP@PVP can inhibit DNA damage repair with spatio-temporal synchronization. NP@PVP is demonstrated to exhibit higher sensitization enhancement ratio (SER) of 2.29 and excellent tumor ablation capability upon irradiation in vivo in comparison with cisplatin (SER of 1.78). Our strategy demonstrates that the RT sensitization effect of bismuth and cisplatin based NP@PVP has great anticancer potential in chemo-radiation synergistic therapy, which is promising for clinical application.

Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation.

INTRODUCTION: Ulinastatin, a broad-spectrum serine protease inhibitor, has been widely used to treat various diseases clinically. However, so far, the antinociceptive effect of ulinastatin remains less studied experimentally and the underlying mechanisms of ulinastatin for pain relief remain unclear. This study aimed to find evidence of the analgesic effect of ulinastatin on acute somatic and visceral pain. METHODS: The analgesic effect of ulinastatin on acute somatic and visceral pain was evaluated by using formalin and acetic acid-induced writhing test. The analgesic mechanism of ulinastatin was verified by detecting the peripheral inflammatory cell infiltration and spinal glial activation with hematoxylin-eosin (H&E) and immunohistochemistry staining. RESULTS: We found that both of intraperitoneal (i.p.) pre-administration and post-administration of ulinastatin could reduce the total number of flinching and the licking duration following intraplantar formalin injection in a dose-related manner. However, the inhibitory effect of ulinastatin existed only in the second phase (Phase 2) of formalin-induced spontaneous pain response, with no effect in the first phase (Phase 1). The formalin-induced edema and ulcer were also improved by i.p. administration of ulinastatin. Moreover, i.p. administration of ulinastatin was also able to delay the occurrence of acetic acid-induced writhing and reduced the total number of writhes dose-dependently. We further demonstrated that ulinastatin significantly decreased the local inflammatory cell infiltration in injured paw and peritoneum tissue under formalin and acetic acid test separately. The microglial and astrocytic activation in the spinal dorsal horn induced by intraplantar formalin and i.p. acetic acid injection were also dramatically inhibited by i.p. administration of ulinastatin. CONCLUSION: Our results for the first time provided a new line of evidence showing that ulinastatin could attenuate acute somatic and visceral pain by inhibiting the peripheral and spinal inflammatory reaction.

Cost­effectiveness Analysis of Helicobacter pylori Eradication Therapy in First-Degree Relatives of Patients with Gastric Cancer.

BACKGROUND: Helicobacter pylori (H. pylori) eradication therapy has been shown to reduce the risk of gastric cancer in patients who have a family history of gastric cancer in first-degree relatives. The aim of this study was to assess the cost-effectiveness of H. pylori eradication therapy in a select population in the People's Republic of China. METHODS: A Markov model was applied to evaluate the cost-effectiveness of H. pylori eradication therapy. The long-term costs of H. pylori eradication therapy were calculated from the Chinese perspective. Health outcomes were measured by quality-adjusted life years (QALYs). Epidemiological information and health utilities used in the model were collected from published literatures or statistical bureaus. A sensitivity analysis was conducted to explore the influence of parameters on the uncertainty of the model. RESULTS: Compared with the no eradication therapy group, H. pylori eradication therapy prolonged an average of 4.52 QALYs (32.64 QALYs vs 28.12 QALYs) and saved $3227.07 ($2472.83 vs $5699.90). The cost-effectiveness analysis demonstrated that no H. pylori eradication therapy cost more and produced less QALYs. It was dominated by H. pylori eradication therapy. The one-way sensitive analyses proved that the results were robust to the fluctuations of the input parameters. CONCLUSION: H. pylori eradication therapy not only reduced the risk of gastric cancer in first-degree relatives of patients with gastric cancer but also was an economical strategy with lower costs and greater efficacy.

Cost-Effectiveness Analysis of Maintenance Olaparib in Patients with Metastatic Pancreatic Cancer and a Germline BRCA1/2 Mutation Based on the POLO Trial.

OBJECTIVE: The phase III POLO trial demonstrated that olaparib as maintenance therapy for metastatic pancreatic cancer patients with a germline BRCA mutation had greater efficacy than placebo, but maintenance olaparib places an economic burden on patients. This study evaluated the cost-effectiveness of olaparib as maintenance therapy based on the POLO trial (NCT02184195). METHODS: A three-state Markov model (progression-free survival [PFS], progressive disease [PD] and death) based on data from the POLO trial was used to estimate the incremental cost-effectiveness ratio (ICER) of maintenance olaparib versus placebo for metastatic pancreatic cancer patients with a germline BRCA mutation. The cost was evaluated from the Chinese society's perspective, and health outcomes were assessed in terms of quality-adjusted life years (QALYs). The primary outcome was the ICER gained in terms of 2019 US$ per QALY. Model robustness was explored with one-way and probabilistic sensitivity analyses. RESULTS: Compared with placebo, maintenance olaparib increased costs by $23,544.35 while gaining 0.69 QALYs, resulting in an ICER of $34,122.25 per QALY. The ICER was far higher than the commonly accepted willingness-to-pay threshold ($28,255.55 per QALY). CONCLUSION: Compared with placebo, maintenance olaparib for metastatic pancreatic cancer patients with a germline BRCA mutation is not cost-effective in China.

A Multicellular Network Mechanism for Temperature-Robust Food Sensing.

Responsiveness to external cues is a hallmark of biological systems. In complex environments, it is crucial for organisms to remain responsive to specific inputs even as other internal or external factors fluctuate. Here, we show how the nematode Caenorhabditis elegans can discriminate between different food levels to modulate its lifespan despite temperature perturbations. This end-to-end robustness from environment to physiology is mediated by food-sensing neurons that communicate via transforming growth factor ß (TGF-ß) and serotonin signals to form a multicellular gene network. Specific regulations in this network change sign with temperature to maintain similar food responsiveness in the lifespan output. In contrast to robustness of stereotyped outputs, our findings uncover a more complex robustness process involving the higher order function of discrimination in food responsiveness. This process involves rewiring a multicellular network to compensate for temperature and provides a basis for understanding gene-environment interactions. Together, our findings unveil sensory computations that integrate environmental cues to govern physiology.

An automated platform to monitor long-term behavior and healthspan in Caenorhabditis elegans under precise environmental control.

Health and longevity in all organisms are strongly influenced by the environment. To fully understand how environmental factors interact with genetic and stochastic factors to modulate the aging process, it is crucial to precisely control environmental conditions for long-term studies. In the commonly used model organism Caenorhabditis elegans, existing assays for healthspan and lifespan have inherent limitations, making it difficult to perform large-scale longitudinal aging studies under precise environmental control. To address these constraints, we developed the Health and Lifespan Testing Hub (HeALTH), an automated, microfluidic-based system for robust longitudinal behavioral monitoring. Our system provides long-term (i.e. entire lifespan) spatiotemporal environmental control. We demonstrate healthspan and lifespan studies under a variety of genetic and environmental perturbations while observing how individuality plays a role in the aging process. This system is generalizable beyond aging research, particularly for short- or long-term behavioral assays, and could be adapted for other model systems.