Therapy Research Articles

LPCAT1, the Enzyme Responsible for Converting LPC to PC, Promotes OPC Differentiation InVitro.

Myelin is the key structure for high-speed information transmission and is formed by oligodendrocytes (OLs) which are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system. Lipid is the main component of myelin and the role of lipid metabolism-related molecules in myelination attach increasing attention. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) mediates the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC), and its role in myelination draws our interest as LPC is a classical demyelination inducer and PC is a major component of myelin. In this work, LPCAT1 is found expressed in the oligodendrocyte lineage cells during myelination. Invitro experiments showed that the expression level of LPCAT1 gradually increased along with the differentiation process from OPCs to OLs, and over-expression and interference experiments showed that LPCAT1 promoted OPCs differentiation without affecting their proliferation or apoptosis. Mechanistically, the undertaker of LPCAT1's pro-differentiation role is not PC, but the phosphorylated mTOR which is a key regulator in OPCs differentiation. RNA sequencing analysis showed LPCAT1 promoted the expression of ZBTB20 which is an important transcription factor related to lipid metabolism and regulates mTOR phosphorylation. Invivo, complex myelin tomacula involving multiple axons was formed after conditionally knocking out LPCAT1 in oligodendrocyte lineage cells, but no obvious myelin thickness abnormalities were observed. Our results indicate that LPCAT1 is an important regulator of myelination, and lipid metabolism-related molecules may be new valuable targets for the treatment of diseases with myelin abnormalities.

The Impact of Active Ascertainment on Sex-Specific Differences in the Prevalence and Phenotype of Transthyretin Cardiac Amyloidosis: The SCAN-MP Study

Transthyretin cardiac amyloidosis (ATTR-CA) is disproportionately diagnosed in older adult men. However, studies suggest that the true prevalence of ATTR-CA in women may be higher than previously reported. The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study utilizes nuclear scintigraphy to identify ATTR-CA in self-identified Black and Caribbean Hispanic participants ≥60 years old with heart failure and left-ventricular hypertrophy. We characterized the sex distribution and phenotypic characteristics of ATTR-CA in this active ascertainment cohort in comparison to a population of ATTR-CA patients who were referred to a tertiary care academic center outpatient clinic. Compared to the referral clinic cohort, the active ascertainment SCAN-MP cohort had a greater proportion of women (31.3% vs 13.3%, p=0.016). This was mainly attributed to the higher proportion of women with wild-type disease [ATTRwt-CA] (27.8% vs 7.1%, p=0.012). Women with ATTR-CA in the active ascertainment cohort exhibited higher left ventricular ejection fraction than those in the referral cohort (61% vs 50%, p = 0.011); lower left ventricular mass index (110 g/m2 vs 148 g/m2, p = 0.014); and lower posterior wall thickness (1.4 cm vs 1.6 cm, p = 0.01). An active ascertainment strategy for ATTR-CA identification demonstrated a greater proportion of women than did a referral cohort, driven predominantly by the greater proportion of women with ATTRwt-CA, and echocardiographic evidence of a less severe phenotype. In conclusion, efforts for early identification of ATTR-CA in women are critical for reducing sex disparities in this clinically treatable disease.

Efficacy and safety of Shexiang Baoxin Pill (MUSKARDIA) in patients with stable coronary artery disease across different weight subgroups.

Shexiang Baoxin Pill (MUSKARDIA), a traditional Chinese patent medicine, plays a crucial role in both preventing and treating diverse cardiovascular diseases, including coronary heart disease, myocardial infarction (MI), and heart failure. Preclinical research has demonstrated that the cardioprotective effects of MUSKARDIA are achieved through multiple pathways, such as enhancing coronary artery dilation, fostering new blood vessel growth, reducing inflammation and oxidative stress, improving lipid metabolism, and protecting vascular endothelium. This subgroup analysis aimed to evaluate the efficacy and safety of Shexiang Baoxin Pill (MUSKARDIA) plus optimal medical therapy (OMT) across different weight categories in treating stable coronary artery disease (CAD). This investigation was a subgroup analysis of a multicenter, randomized, double-blind, placebo-controlled phase IV clinical study. Patients receiving OMT were randomly assigned to either MUSKARDIA or placebo group for a 24-month period. This analysis focused on body weight as a distinguishing factor, using 65kg as the cutoff. The primary efficacy endpoint was the composite of major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. Secondary efficacy endpoint comprised a composite of all-cause mortality, non-fatal MI, non-fatal stroke, hospitalizations for unstable angina or heart failure, and coronary revascularization procedures. A total of 2646 patients were included in the analysis, with 916 patients weighing less than 65kg and 1730 patients weighing 65kg or more. The median ages were 68 (range: 35-90) years and 62 (range: 29-90) in these two subgroups, respectively. For patients weighing less than 65kg, the MUSKARDIA group exhibited a significantly lower incidence of the primary efficacy endpoint (0.65%) compared to the placebo group (2.64%) (P=0.018), with a reduced risk of MACEs (HR=0.241, 95%CI: 0.068-0.856; P=0.0168). Conversely, in patients weighing 65kg or more, no significant differences were observed in the incidence rates or risks of primary or secondary efficacy endpoints between the MUSKARDIA and placebo groups (All P>0.05). Adverse events were similar between two groups across both weight subgroups. MUSKARDIA plus OMT demonstrated promising efficacy and acceptable safety in CAD patients weighing less than 65kg, potentially reducing the risk of MACEs. For patients weighing 65kg or more, further investigation is needed to optimize dosing strategies.

Safety and Tolerability of Initiating Sacubitril-Valsartan With Spironolactone During Hospitalization for Acute Decompensated Heart Failure

Background: Initiation of sacubitril-valsartan and mineralocorticoid receptor antagonists (MRA) during hospitalization for acute decompensated heart failure (ADHF) may be an ideal time to optimize guideline-directed medical therapy. However, there is limited research assessing the safety of combining these agents in the hospital. Methods: This was a multi-center, retrospective, propensity-score matched cohort study performed at 7 acute-care hospitals within a large health care system. All adult patients admitted with ADHF between January 1, 2019 to December 31, 2021 who received sacubitril-valsartan with MRA (MRA group) or without MRA (non-MRA group) and had a left ventricular ejection fraction (LVEF) < 40% were included in the study. Results: 220 patients were screened during the study time frame with 179 meeting inclusion criteria. Following propensity-score matching, 50 patients in the MRA group were matched to 50 patients in the non-MRA group. The overall incidence of adverse drug reactions (ADRs) was 24% in the non-MRA group compared to 20% in the MRA group (P = .629). There was a significantly greater incidence of hyperkalemia in the MRA group (0% vs 10%; P = .022). None of the patients in the non-MRA group were readmitted within 30 days due to an ADR compared to 6% in the MRA group (P = .079). Conclusion: The addition of spironolactone to sacubitril-valsartan in the hospital setting following stabilization of ADHF did not lead to a significantly greater incidence of overall ADRs, but patients were more likely to develop hyperkalemia and there was a numerically higher incidence of 30-day readmissions due to ADRs.

Investigating the frequency of neural autoantibodies in refractory focal epilepsy.

There have been conflicting reports about the frequency of neural autoantibodies in epilepsy cohorts, which is confounded by the lack of clear distinction of epilepsy from acute symptomatic seizures due to encephalitis. The aim of this study was to determine the frequency of neural autoantibodies in a well characterised population of refractory focal epilepsy of known and unknown cause. Cases were recruited from epilepsy outpatient clinics at the Princess Alexandra, Mater, Royal Brisbane and Women's and Cairns Base Hospitals from 2021 - 2023. Included cases were refractory to medical therapy, met the ILAE definition of focal epilepsy and were characterised using anatomo-electro-clinical correlation. Cases with prior encephalitis, inflammatory neurological disease or prior parenchymal brain insults were excluded. A total of 100 patients were recruited. No cases with clinically significant neural autoantibodies were discovered. One was positive for serum anti-NMDAR antibodies, however autoantibodies were absent from CSF. Cases were also screened using a predictive score (McGinty et al.). From this, 2 cases were identified as seronegative autoimmune associated epilepsy and demonstrated significant reduction in seizure frequency with administration of immunotherapy. These cases had common features including temporo-perisylvian semiology especially ictal piloerection and high seizure frequency. Clinically relevant neural autoantibodies are uncommon in well characterised chronic focal epilepsy populations. Despite this there are isolated cases that still demonstrate improved seizure control with the use of immunotherapy. Such cases highlight the need for further studies to understand the role of immunity in novel pathophysiological mechanisms in epilepsy.

Chest pain and coronary artery disease in cardiac amyloidosis: Prevalence, mechanisms, and clinical implications.

Amyloidosis is a systemic disease affecting multiple organs, and often presents with cardiac involvement, with 2 primary underlying pathologies: amyloid light chain- and transthyretin cardiac amyloidosis. Chest pain can occur in both types with variable clinical presentations. This narrative review describes the relationship between cardiac amyloidosis (CA) and chest pain. A PubMed search (June 03. 2024) identified 393 articles related to chest pain in CA. Twenty-eight studies, in English and with full text, were selected. Articles included were case reports, reviews, perfusion- and autopsy studies. In CA patients 10%-20% report chest pain as the initial symptom preceding the diagnosis, and the overall prevalence of chest pain is 38% of patients with CA and it is related to an increased risk of heart failure hospitalization. The mechanisms leading to chest pain in CA patients include increased left ventricular diastolic pressure, infiltration of amyloid fibrils inside and around coronary arteries, and amyloid compression of the microvasculature. The mechanisms commonly lead to elevations of plasma troponin levels, which are higher in amyloid patients with chest pain compared to amyloid patients without chest pain. Symptomatic treatment of chest pain can be challenging due to the low tolerability of medical therapy and poor outcomes of coronary interventions in alleviating the pain and with a higher rate of complications. Our review underscores the importance of recognizing chest pain as a CA symptom, particularly in the elderly. Persistent troponin elevation without coronary artery disease could indicate CA. Screening-based and longitudinal studies are crucial for understanding the relationship between chest pain and CA. Acknowledging the significance of chest pain in CA may facilitate early intervention and improve patient outcomes.

Quality of care delivery in patients with acute heart failure: insights from the international REPORT-HF registry.

Heart Failure (HF) quality of care (QoC) is associated with clinical outcomes. Therefore, we investigated differences in HF QoC across worldwide regions (with differing national income) and the association of quality indicators with outcomes. We examined the quality of care (QoC) in acute heart failure (HF) patients across different regions using quality indicators (QIs) from the European Society of Cardiology (ESC) and the American Heart Association (AHA) to evaluate QoC. The analysis included 17,632 patients enrolled from 358 medical centres in 44 countries between 23 July 2014 and 24 March 2017, all part of the prospective REPORT-HF cohort study. We investigated how QoC varied by region and its relationship with mortality rates at 30 days and 1 year after hospital discharge. For each QI, percentage attainment of QI among eligible patients was calculated and compared across regions. Among 17,632 patients (median age: 67 years; 61% women) followed up for a median of two years, we assessed 16 QIs. QIs that were least often achieved included measurement of natriuretic peptides, performance of echocardiography, treatment with guideline medical therapy, and a scheduled follow-up consultation after discharge. QI achievement was significantly lower in lower-than higher-income countries. Higher (≥50% vs. <50%) achievement of cumulative QIs was associated with lower 30-day (hazard ratio [HR] 0.58, 95% Confidence Interval [CI] 0.40-0.83; p<0.001), and 1-year mortality (HR 0.58, 95% CI 0.50-0.68; p<0.001). QoC is lower in lower-than higher-income countries and lower QoC is associated with worse outcomes. Improving QoC by addressing structural barriers and quality improvement programs may improve the outcomes of patients with HF. Novartis.

Prophylaxis by a reversible cholinesterase inhibitor and the NMDA receptor antagonist treatment as combinatorial countermeasure against nerve agent poisoning in mice model.

The current pharmacological pretreatment and medical treatment of nerve agent poisoning is an insufficiently addressed medical task. The prophylactic efficacy of a novel compound acting dually as an acetylcholinesterase inhibitor and NMDA receptor antagonist (K1959) and the therapeutic efficacy of a novel NMDA receptor antagonist (K2060) were evaluated in the NMRI mice model of nerve agent poisoning by tabun, soman and sarin. Their added value to the standard antidotal treatment (a combination of oxime reactivator and atropine) was also analyzed. The novel dually acting prophylactic drug (K1959) did not bring any additional benefit compared to the commonly used pyridostigmine. By contrast, an increase in the therapeutic efficacy of classic antidotal treatment was observed when the novel NMDA receptor antagonist (K2060) was combined with commonly used antidotes (oxime reactivator in combination with atropine). This novel combination reduced the acute toxicity of tabun, soman, and sarin more than two-fold, four-fold, and five-fold, respectively. These results highlight the possibility of NMDA antagonists such as K2060 as a supportive drug for the classic therapy of organophosphorus poisoning.

Socioeconomic position, psychiatric medical treatment and risk of breast cancer recurrence and mortality: A Danish population-based cohort study.

Breast cancer patients with low socioeconomic position (SEP) have a higher risk of recurrence and mortality. We examined the extent to which prior psychiatric medication impacted this association. We conducted a cohort study of premenopausal women diagnosed with breast cancer in Denmark from 2002 to 2011 (n = 5847), linking data from Denmark's nationwide population-based health registries on breast cancer diagnosis, treatment, psychiatric medication prescriptions and SEP indicators (marital status, cohabitation, income, education and employment). We followed the women up to 10 years from breast cancer diagnosis until recurrence, death, emigration, other malignancy, or September 2017. We used Cox regression to estimate hazard ratios (HRs) and corresponding 95 % confidence intervals (95 %CI) associating each SEP indicator with recurrence and all-cause mortality. To evaluate interaction by psychiatric medication use on the association between SEP and prognosis, we 1) stratified the models according to prior use of psychiatric medication and 2) added an interaction term to the regression model. Women with short compared with intermediate education level and prior psychiatric medication had increased risk of recurrence (HR = 1.41, 95 %CI = 1.05-1.91); this was higher than seen in those without prior psychiatric medication (HR = 1.06, 95 %CI = 0.87-1.29). Patterns were similar for all-cause mortality. Likewise, unemployed women with a history of psychiatric medication use had a higher risk of all-cause mortality (HR = 1.74, 95 %CI = 1.31-2.31) compared to unemployed women without prior psychiatric medication use (HR = 1.32, 95 %CI = 1.03-1.70). In contrast, prior psychiatric medication use did not have a negative impact on breast cancer prognosis in women who were single, living alone or had low income. Breast cancer patients with prior psychiatric disease who have short education or are unemployed may be particularly vulnerable to recurrence and mortality. These women may benefit from more frequent follow up examinations.

Behaviours and drivers of diagnosis-related group upcoding in China: A mixed-methods study.

As a highly destructive gaming behaviour in Diagnosis-Related Group (DRG), upcoding has garnered increasing scholarly attention. This study considers the prevalence, types and risk characteristics of upcoding during the pilot implementation of DRG payments in China, and it also explores the drivers of upcoding and provides corresponding policy recommendations for improving the system. Quantitative research data were sourced from the DRG payment audit database in City Z between the dates of June 1, 2019 and May 31, 2020, encompassing audit results comprising 200 medical records randomly selected from 28 hospitals. Qualitative research methods were used, including semi-structured interviews conducted with 10 stakeholders with interests in the DRG payment system, and thematic framework of the consequent data. 5,157 (92.01%) valid records were re-abstracted. 666 (12.91%) evaluated records were found to be upcoded, resulting in an additional payment at a rate of 45.27%. Several factors emerged as shedding light on the probability of upcoding, including cases with comorbidities, those undergoing non-operating room procedures and internal medical treatments, cases in for-profit hospitals and cases in tertiary hospitals. The main drivers of upcoding were found to be financial and administrative pressures, dysfunctional attitudes towards upcoding, technical facilitation and lack of supervision. This paper provides a comprehensive analysis of the behaviours and drivers of DRG upcoding in China, considering the unique hospital management system and incentive mechanisms in place. The results demonstrate that, following the initiation of the DRG payment system, providers have begun to engage in upcoding behaviour under various drivers, leading to additional health care expenditures and undermining the effectiveness of the scheme. In terms of mounting a response to this behaviour, understanding it and what drives it can aid in its prevention. This study suggests implementing intelligent audits to strengthen supervision and supporting hospitals in cost management.

Using Therapeutic Play to Increase the Oral Administration Adherence Rate of Preschool Pediatric Inpatients

Oral administration is the most common mode of medical treatment for pediatric patients. Although over 98% of the patients in the targeted pediatric unit require oral medication, the oral administration adherence rate in 2022 was 43.9%. The reasons for this low rate were identified as: (1) no relevant oral administration educational materials, (2) no relevant continued nursing education provided, and (3) lack of assistive tools and feeding aids to help administer oral medication to young children. This project was developed to increase the adherence rate of oral administration of preschool pediatric inpatients in our hospital. The improvement strategies included the design of patient-centered oral medication care guidance leaflets and QR code (quick response code) video links, the development of therapeutic play aids, adding cartoon characters to medicine feeders, and the creation of a "Rescue the Forest" picture book and video and reward stickers. The oral medication adherence rate increased from 43.9% pretest to 91.9% posttest. This project and its positive effect on the rate of oral medication adherence may be referenced by other pediatric units.

Pharmacotherapy of Psychological Disorders Using Psychedelic Drugs: A Treatise for Psychiatrists

: Psychedelics are currently being examined once more as potential remedies for untreatable biological illnesses after decades of research problems. They are frequently regarded to be physically safe and do not frequently lead to dependency or addiction. The use of psychedelic substances in the treatment of mental illness and the adoption of the Substance Act of 1970 has classified psychedelic drugs as Schedule I. The major objective of this review is to highlight the prospective use of specific psychedelic medicines, such as psilocybin, LSD, MDMA, and ayahuasca, in the treatment of various psychiatric conditions, such as treatment-resistant depression, post-traumatic traumatic stress, end-of-life anxiety, and substance misuse disorders. As documented from both animal and human studies, in addition, there will be a study of the effectiveness and safety. The body of research suggests that psychedelics may one day offer revolutionary treatments for mental diseases, contrary to conventional therapy. However, given their distinctive histories and a high potential for abuse with widespread distribution, more care and effort must be given to protect their use as efficient medical treatments instead of drugs of abuse.

Chapter 14: Post surgical follow-up of primary hyperparathyroidism.

Primary hyperparathyroidism is treated surgically. Postoperatively, close monitoring of blood calcium levels is necessary to detect any hypocalcemia. Postoperative PTH assays can be performed within 24hours to identify patients who will not develop permanent hypoparathyroidism. Hypocalcemia may be caused by hypoparathyroidism (especially in the case of multi-glandular surgery or revision surgery) or by hungry bone syndrome. The latter should be suspected in case of major skeletal damage or severe preoperative vitamin D deficiency. It leads to severe hypocalcemia with normal or elevated PTH concentration, hypophosphatemia, hypomagnesemia, and low calciuria despite high doses of calcium and 1-25 OH vitamin D. Treatment of postoperative hypocalcemia depends on severity, symptoms and surgical procedure. In uni-glandular surgery, symptomatic treatment with calcium alone is recommended (0.5 to 1g/day). In multi-glandular involvement or repeat surgery, treatment with calcium (1 to 3g/day) is recommended if hypocalcemia is symptomatic or profound (<1.9mmol/L) (i.e. 76mg/L). If it is insufficient, the potential contribution of active vitamin D treatment should be assessed with an endocrinologist. If hypocalcemia is treated, patients should preferably be monitored by an endocrinologist (blood calcium level, calciuria and possibly phosphatemia and PTH). Under medical treatment of hypoparathyroidism, blood calcium levels should be monitored at least every 3 months for the first year, then at least twice a year.

Intensive Care Unit Memories and Trauma Triggers for Acute Respiratory Distress Syndrome Survivors Hospitalized During the COVID-19 Pandemic.

Intensive care unit (ICU) admissions can be traumatic for critically ill, ventilated acute respiratory distress syndrome (ARDS) patients due to fear of death, an inability to verbally communicate, reliance on health care professionals, and invasive medical interventions. Adult ARDS patients hospitalized during the COVID-19 pandemic were strictly isolated and had limited to no visitation from loved ones, impacting their access to support systems. To explore the memories and sensory triggers for them (if applicable) of adult ARDS survivors hospitalized during the COVID-19 pandemic. This study used a phenomenological design with an interpretative descriptive approach. Semistructured interviews with open-ended questions were conducted with survivors. Thematic analysis of 16 ARDS survivors' responses to ICU memories and sensory triggers questions was completed to identify the most prevalent themes. Major themes for vivid memories included (1) altered reality, (2) vivid nonsense dreams, (3) medical treatment/procedures, and (4) feeling lonely/isolated. Themes for triggers included (1) seeing doctors/nurses/hospitals and medical equipment or seeing/hearing media depictions of them, (2) hearing ringtones and beeping/alarms, (3) seeing/hearing helicopters, (4) smelling cleaning products, and (5) seeing/touching scars. Fifteen of the 16 ARDS survivors reported traumatic vivid memories, often triggered by sensory stimuli they encountered in their everyday lives. It is important for acute care and outpatient nurses to understand the impact of an ICU admission on ARDS survivors' mental health, so they can adopt evidence-based interventions to prevent or limit these effects.

The bitter flavor of Banxia Xiexin decoction activates TAS2R38 to ameliorate low-grade inflammation in the duodenum of mice with functional dyspepsia.

Banxia Xiexin Decoction (BXD) is a traditional herbal formulation with a bitter flavor that has a long-standing history of use in Asia for treating functional dyspepsia (FD). In traditional Chinese medicine, the bitter flavor is believed to play a critical role in the therapeutic activity of BXD. The ethnopharmacological properties of bitter plant extracts are closely associated with their anti-inflammatory effects, which may contribute to their efficacy in FD. However, the specific mechanisms remain unknown. The objective of this study is to uncover the bitter active compounds of BXD and their effects in the treatment of FD. The chemical compounds of BXD were identified using HPLC-Q-Exactive-MS. Active compounds in BXD were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and bitter active compounds were further identified using BitterDB and PlantMolecularTasteDB. Molecular docking was employed to identify potential targets of these bitter active compounds, and their activation was validated through flow cytometry analysis of Ca2+. Subsequently, a mouse model of FD was established, and our hypothesis was further validated using enzyme linked immunosorbent assay, immunohistochemistry, immunofluorescence, and western blotting. Through HPLC-Q-Exactive-MS analysis, TCMSP, BitterDB, and PlantMolecularTasteDB database, a total of 11 bitter active compounds in BXD were identified: Baicalein, Baicalin, Berberine, Coptisine, Formononetin, Isorhamnetin, Kaempferol, Naringenin, Palmatine, Quercetin, and Wogonin. Molecular docking results indicated that these active compounds exhibited strong affinity for TAS2R38, with Berberine showing the highest scoring. Flow cytometry analysis of Ca2+ revealed that both Berberine and BXD elevated intracellular calcium concentrations, although this effect was partially antagonized by the TAS2R38 inhibitor probenecid. In vivo experiments demonstrated that BXD effectively improved eosinophil infiltration in the duodenum of FD mice, downregulated the expression of inflammatory factors IL-1β, IL-5, and TNF-α, inhibition of NF-κB signaling pathway activation, alleviated damage to the duodenal mucosal barrier, and reversed gastrointestinal motility disorders, with the therapeutic effect enhancing with increasing doses of BXD. However, this therapeutic effect was partially inhibited following probenecid intervention. BXD contains numerous bitter active compounds that play a significant role in regulating inflammatory activity in the duodenum of FD through the activation of TAS2R38. This finding unveils, for the first time, the ethnopharmacological activity of bitter plant taste agents in anti-inflammatory effects, providing new insights for the treatment and drug development of FD.

Evaluating novel therapies and circulating tumor DNA (ctDNA) as a marker of response in curatively treated gastrointestinal cancers with microscopic residual disease.

TPS850 Background: ctDNA can identify the earliest sign of relapse (MRD) after curative therapies with specificities of 93-100%, positive predictive values over 95%, and median lead times of 8-9 months before radiographic relapse. ctDNA has identified a "new stage" of high-risk patients (pts) with no evidence of disease radiographically (rNED) and MRD who lack treatment (tx) strategies as, traditionally, they wait for radiographic progression of disease (POD) before starting therapies. Treating MRD is a promising strategy supported by observational studies where ctDNA clearance is linked with improved survival and on-tx kinetics predict drug efficacy . We designed a pilot investigator-initiated trial to 1) determine the feasibility of using ctDNA as a rapid signal for positive therapeutic activity and 2) obtain pilot data on the efficacy of a novel combination therapy (atezolizumab [A] + bevacizumab [B]) in eradicating MRD in previously curatively treated pts with GI cancers. Methods: We will enroll 20 pts with any-stage cancers divided over 4 cohorts (n=5 colorectal [CRC], n=5 hepatocellular/biliary tract carcinoma, n=5 upper GI, n=5 pancreatic adenocarcinoma) who have a positive Signatera ctDNA test and rNED any time after completing standard curative therapies. Pts are treated with A 1200 mg IV + B 15 mg/kg IV on day 1 of a 21-day cycle for up to 1 year with imaging every 12 weeks and serial ctDNA testing every 3 weeks. Co-primary endpoints are rates of pt enrollment in 12 months and rates of ctDNA responses at a 12-week landmark after tx initiation. Pts with ctDNA POD (ctDNA doubling on each of 2 sequential tests, any rate of rise in 3 sequential tests, or radiographic relapse) will stop while those with ctDNA complete response (CR; clearance on 2 sequential tests + ongoing rNED) or ctDNA partial/stable response (PR; not ctDNA CR or POD + ongoing rNED) will continue tx. Each cohort's Bayesian predictive probability of positive therapeutic activity will be calculated. If at least 60% of a cohort experiences ctDNA CR, it will be expanded by 5 pts. This scenario is equivalent to Simon's 2-stage Minimax design testing a null hypothesis of 20% CR vs. an alternative hypothesis of at least 60% CR at 5% alpha with 80% power. If at least 5/10 pts in an expanded cohort experience ctDNA CR, this will generate interest in developing a larger confirmatory trial to evaluate pt survival outcomes with A+B and ctDNA as a surrogate for survival. Secondary endpoints are toxicity and enrollment barriers. Exploratory endpoints are associations between ctDNA conversion and disease-free survival, tumor whole exome sequencing data, and peripheral blood immune profiles collected at baseline and on tx. Enrollment began in Q1 2023, paused in 7/2023 due to funding changes, and re-opened 8/2024 with 5 patients enrolled currently (n=4 CRC, n=1 biliary). Clinical trial information: NCT05482516 .

Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

367 Background: Recently, PD-1 blockades combined with dual chemotherapy regimens in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might offer a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Sep 2024, a total of 30 patients were enrolled, with 29 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (3.4%), 23 PR (79.3%), 2 SD (6.9%) and 3 NE (10.3%). Therefore, the preliminary ORR was 82.8% (95%CI: 64.2%-94.2%), DCR was 89.7% (95%CI: 72.6%-97.8%). The primary median PFS of the 29 patients was 10.84 months (95%CI: 7.57-14.11). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 29 patients with the incidence &gt;20% were anemia (62%), leukopenia (31%), peripheral neurotoxicity (28%) and rash (21%). Common grade ≥3 treatment-emergent adverse events were leukopenia (7%), glutamic-pyruvic transaminase was elevated (3%), glutamic oxalacetic transaminase increased (3%), hypertension (3%), diarrhea (3%) and rash (3%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials. Clinical trial information: ChiCTR2400089133 .

Polyphyllin VII Enhances the Sensitivity of Prostate Cancer Cells to Docetaxel by Promoting Mitochondrial Dysfunction and Inducing Ferroptosis.

Docetaxel (DTX) is the preferred chemotherapeutic drug for prostate cancer (Pca), but the emergence of resistance has significantly reduced its efficacy. Polyphyllin VII (PPVII), a small molecule natural product derived from the traditional herb Paris polyphylla, has shown anticancer potential. This study aims to investigate the effects and mechanisms of PPVII combined with DTX in treating Pca. DTX-sensitive DU-145 cells and DTX-resistant DU145/DTX cells were utilized for experiments in this study. Cell viability was assessed using MTT assays, while apoptosis, cell cycles, and ferroptosis were analyzed through flow cytometry and Western blot. Mitochondrial function was evaluated using immunofluorescence. Additionally, the expression of proteins related to the AMP-activated protein kinase/mammalian target of the rapamycin/S6 kinase (AMPK/mTOR/S6K) signaling pathway was also examined to further investigate the underlying mechanisms. PPVII significantly enhanced the inhibitory effect of DTX, reduced cell viability (p < 0.05), and promoted apoptosis (p < 0.05) and cell cycle arrest (p < 0.05). Specifically, PPVII increased the sensitivity of Pca cells to DTX by inducing ferroptosis and affecting mitochondrial function. Notably, the activation of the AMPK/mTOR/S6K signaling pathway played a crucial role in this process. This study revealed the synergistic effects and potential mechanisms of PPVII combined with DTX in Pca cells, and provided a reference for effectively overcoming DTX resistance in the clinical treatment of Pca.

Recent development of micro-nano carriers for oral antineoplastic drug delivery.

Chemotherapy is widely recognized as a highly efficacious modality for cancer treatment, involving the administration of chemotherapeutic agents to target and eradicate tumor cells. Currently, oral administration stands as the prevailing and widely utilized method of delivering chemotherapy drugs. However, the majority of anti-tumor medications exhibit limited solubility and permeability, and poor stability in harsh gastrointestinal environments, thereby impeding their therapeutic efficacy for chemotherapy. Therefore, more and more micro-nano drug delivery carriers have been developed and used to effectively deliver anti-cancer drugs, which can overcome physiological barriers, facilitate oral administration, and ultimately improve drug efficacy. In this paper, we first discuss the effects of various biological barriers on micro-nano drug carriers and oral administration approach. Then, the development of micro-nano drug carriers based on various biomedical components, such as micelles, dendrimers, hydrogels, liposomes, inorganic nanoparticles, etc. were introduced. Finally, the current dilemma and the potential of oral drug delivery for clinical treatment were discussed. The primary objective of this review is to introduce various oral delivery methods and serve as a point of reference for the advancement of novel oral delivery carriers, with the ultimate goal of informing the development of future clinical applications.

Design, synthesis and biological evaluation of novel diaryl-substituted fused nitrogen heterocycles as tubulin polymerization inhibitors to overcome multidrug resistance in vitro and in vivo.

Microtubule-targeting agents (MTAs) are considered as one of the most successful chemotherapy drugs for lung adenocarcinoma (LUAD). However, the clinical application of MTAs is often significantly plagued by multidrug resistance (MDR). To overcome this limitation in the quest of more effective MTAs for tumor therapy, a series of novel diaryl-substituted nitrogenous fused heterocycles were designed, synthesized and evaluated. Through four rounds of structure-activity relationship studies, the benzoimidazole derivative 37 was identified as a potent cytotoxic agent against both paclitaxel-sensitive and -resistant A549 (A549/T) cells, effectively overcoming multidrug resistance of A549/T cells against various MTAs. Mechanistic investigations revealed that 37 could disrupt microtubule assembly and induce cell cycle arrest at the G2/M phase, and hence trigger the cell apoptosis. Furthermore, 37 was found to be a poor substrate for P-glycoprotein (P-gp), a major contributor to multidrug resistance, and could reduce the level of P-gp in resistant cells, thereby effectively overcoming P-gp-mediated multidrug resistance. Notably, 37 exhibited higher liver microsomal stability and better water solubility than those of the reference combretastatin A-4 (CA-4). In vivo studies using an A549/T xenograft model demonstrated that 37 significantly inhibited tumor growth without obvious toxicity, outperforming the positive controls CA-4 and paclitaxel. As a novel tubulin polymerization inhibitor, compound 37 is marked by potent anticancer activity and remarkable anti-MDR properties. These salient features, coupled with the low toxicity of 37, would render it quite promising as a lead for further drug development towards clinical treatment of multidrug-resistant LUAD.