Modeling and simulation for individualized therapy of amisulpride in Chinese patients with schizophrenia:focus on inter interindi⁃vidual variability,therapeutic reference range and laboratory alert level

OBJECTIVE To explain the high inter-individual variability and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride,a popula⁃tion pharmacokinetic model in Chinese patients with schizophrenia was built based on therapeu⁃tic drug monitoring data to guide individualized therapy.METHODS Plasma concentration data(330 measurements from 121 patients)were ana⁃lyzed using a nonlinear mixed-effects model⁃ing approach with first-order conditional estima⁃tion with interaction(FOCE I).The concentra⁃tions of amisulpride were detected by HPLC-MS/MS.Age,weight,sex,combination medication history and renal function status were evaluated as main covariates.The model was internally val⁃idated using goodness-of-fit,bootstrap and nor⁃malized prediction distribution error.Recom⁃mended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model.RESULTS A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentra⁃tion in Chinese patients with schizophrenia.The population estimates of the apparent volume of distribution(V/F)and apparent clearance(CL/F)were 12.7 L and 1.12 L·h-1,respectively.Age sig⁃nificantly affected the clearance of amisulpride and the final model was as follow:CL/F=1.04×(AGE/32)-0.624(L·h-1).To avoid exceeding the lab⁃oratory alert level(640μg·L-1),the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg per day for patients aged 60 years,800 mg per day for those aged 40 years and 1200 mg per day for those aged 20 years,respectively.CON⁃CLUSION Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions.The model can be used as a suitable tool for designing individual⁃ized therapy for Chinese patients with schizo⁃phrenia.

Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy

Single-cell RNA sequencing(scRNA-seq)is a novel technology that allows transcriptomic analyses of individual cells.During the past decade,scRNA-seq sensitivity,accuracy,and efficiency have improved due to innovations including more sensitive,automated,and cost-effective single-cell isolation methods with higher throughput as well as ongoing technological development of scRNA-seq protocols.Among the variety of current approaches with distinct features,researchers can choose the most suitable method to carry out their research.By profiling single cells in a complex population mix,scRNA-seq presents great advantages over traditional sequencing methods in dissecting heterogeneity in cell populations hidden in bulk analysis and exploring rare cell types associated with tumorigenesis and metastasis.scRNA-seq studies in recent years in the field of breast cancer research have clustered breast cancer cell populations with different molecular subtypes to identify distinct populations that may correlate with poor prognosis and drug resistance.The technology has also been used to explain tumor microenvironment heterogeneity by identifying distinct immune cell subsets that may be associated with immunosurveillance and are potential immunotherapy targets.Moreover,scRNA-seq has diverse applications in breast cancer research besides exploring heterogeneity,including the analysis of cell-cell communications,regulatory single-cell states,immune cell distributions,and more.scRNA-seq is also a promising tool that can facilitate individualized therapy due to its ability to define cell subsets with potential treatment targets.Although scRNA-seq studies of therapeutic selection in breast cancer are currently limited,the application of this technology in this field is prospective.Joint efforts and original ideas are needed to better implement scRNA-seq technologies in breast cancer research to pave the way for individualized treatment management.This review provides a brief introduction on the currently available scRNA-seq approaches along with their corresponding strengths and weaknesses and may act as a reference for the selection of suitable methods for research.We also discuss the current applications of scRNA-seq in breast cancer research for tumor heterogeneity analysis,individualized therapy,and the other research directions mentioned above by reviewing corresponding published studies.Finally,we discuss the limitations of current scRNA-seq technologies and technical problems that remain to be overcome.

Individualized therapy for metastatic renal cell carcinoma

Metastatic Renal Cell Carcinoma(mRCC)is a highly heterogeneous disease that is notoriously difficult to treat successfully.However,the discovery of novel,targeted therapies over the last decade has revolutionized its management.As the therapeutic options continue to evolve,developing a more individualized treatment strategy is of paramount importance.The International mRCC Database Consortium(IMDC)is a prognostic model that is commonly used in trials and clinical settings to risk stratify patients.This allows for optimal therapy selection on a more individual basis.However,the distinct lack of validated predictive biomarkers in mRCC renders it difficult to assess therapy response.An improved understanding of tumor biology and genetics has prompted a shift from cytokine therapy to the use of vascular endothelial growth factor(VEGF)inhibitors,tyrosine kinase Inhibitors,immune checkpoint inhibitors or combination strategies.Studies have identified some putative markers and genetic mutations as potential predictors of therapy response.Early results are promising,and there are many ongoing trials further assessing their suitability for clinical use.This review will evaluate the current treatment landscape and molecular biology of mRCC,with a specific focus on the prognostic and predictive markers available to guide treatment options and further improve patient outcomes.

Application of donor dendric cell mediated recipieut lymphocyte reaction after related kidney transplantation in individualized immunosuppressive therapy

Objective To explore the feasibility of mediating recipient lymphocyte reaction with donor dendritic cells ( Dcs) in renal allograft recipients to guide individualized immunosuppressive therapy. Methods From Jan. 2008 to Jan. 2010,30 recipients received living related kidney transplantation were successively and divided into

Analysis of the personalized treatment and the relevant prognostic factors in children with medulloblastoma

Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According to the risk stratification criteria,the cases were divided into the following four risk groups:low,standard,high,and very high.The 5-year overall survival(OS)and progression-free survival(PFS)rates were summarized.Further,the effects on the prognosis of tumor size,tumor stage,degree of resection,treatment mode,metastatic recurrence,molecular typing,and risk stratification were analyzed.Results:In the present study,following surgery,3 cases abandoned radiotherapy(RT)and chemotherapy(CHT),7 cases(<3 years of age)received only CHT,and 22 cases received combined RT and CHT.Total and near-total tumor resections were performed in 29 cases(90.6%).Subtotal resections were performed in 3 cases,and there were no surgery-related deaths.The average follow-up duration was 47 months.The average 5-year PFS and OS rates were 57.3%±7.2%and 68.7%±8.6%,respectively.The OS and PFS rates were significantly correlated with tumor-risk stratification,molecular staging,tumor stage,treatment mode,and recurrence after surgery(p<0.01).The degree of tumor resection,pathological type,and the presence of preoperative implantation were secondary factors affecting the prognosis(p<0.05).Age was correlated with the PFS rate.There was no correlation between age/tumor location/tumor size and prognosis(p>0.05).Favorable prognostic factors in the low-and standard-risk groups were stage M0,wingless-type MB,postoperative RT combined with CHT,no postoperative recurrence,age≥3 years,and total tumor resection.Conclusions:Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.

Recent applications of chemosensitivity tests for colorectal cancer treatment

The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer(CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culturebased chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyltetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC.

Individual Care Pathways in the Context of Complex Therapeutic System--Therapeutic Model and Case Report

A complex multifactorial therapeutic system was established and developed during the past three years. Here present the basic approach and the individualized therapeutic strategies of this therapeutic system by examples of specific case reports. The aim of the study is to point out to the real mission of our outpatient care, namely psycho-social reintegration that is achieved by a therapy with a unique pattern. Case reports： 1. A 59-year-old female patient suffering from psychosomatic muscular tension, which started two years ago. After a partially effective cognitive-behavioral therapy a severe traumatic event in the patient＇s past in connection with the symptoms was revealed, then the trauma was processed via psychodynamic approach. 2. A 56-year-old female patient suffering from psychosomatic symptoms and depression went through a therapeutic healing process, which focused on the development and maturation of her personality （from a ＂child＂ to an ＂adult＂）. Conclusion： All the processes of the complex group-centered dynamic therapy proved more effective compared to the classic static relationship between the psychiatrist and the patient. The multifocal therapy is appreciated more and more in parallel to the experiences gained, making it easier to establish and strengthen the therapeutic alliance. The patients have positive feelings about the help given and the possibilities offered. The author＇s therapeutic team is appreciated by the patients and they regard the author＇s center as a peaceful location of their lives being under cover, where voluntarily and willingly they can participate in the individualized therapy with great success.

Revolutionizing preclinical research for pancreatic cancer:the potential of 3D bioprinting technology for personalized therapy

Pancreatic cancer(PC)is a prevalent digestive malignancy worldwide and ranks as the fourth leading cause of cancer-related deaths globally.The incidence and mortality rates have been increasing annually,and due to its insidious onset and high malignancy,most patients are diagnosed at an advanced stage,with a 5-year survival rate of less than 8%(1).PC can be classified into endocrine and exocrine tumors,with over 95% of pancreatic malignant tumors originating from the exocrine portion of the pancreas.

DIAGNOSIS AND TREATMENT OF CESAREAN SCAR PREGNANCY

Objective To investigate the early diagnosis and treatment of cesarean scar pregnancy （CSP）. Methods Clinical data of 28 patients with CSP in Peking Union Medical College Hospital from January 1994 to April 2007, including age, interval from the last cesarean delivery to diagnosis, clinical presentation, location of the lesion, process of diagnosis and treatment, outcome, and follow-up, were retrospectively analyzed. Re, salts CSP constituted 1.05 % of all ectopic pregnancies, and the ratio of CSP to pregnancy was 1 ： 1 221. The mean age of the group was 31.4 years. Twenty-six women had only one prior cesarean delivery. The interval from the last cesarean delivery to diagnosis ranged from 4 months to 15 years. The most common presenting symptoms of CSP were amenorrhoea and vaginal bleeding. Seventeen cases were misdiagnosed as early intrauterine pregnancies and 2 were misdiagnosed as gestational trophoblastic tumor. The other 9 were diagnosed definitely before treatment. The diagnosis was made based on cesarean delivery history, gynecologic examination, ultrasound, and magnetic resonance imaging （MRI）. The treatment of CSP included systemic or local methotrexate administration, conservative surgery, and hysterectomy. The conservative treatment was successful in 24 cases. All of the 28 women were cured through individual therapies. Conclusions CSP is rare and usually misdiagnosed as other diseases. Ultrasound is valuable for diagnosing CSP, and MRI can be used as an adjunct to ultrasound scan. Early diagnosis offers the options of conservative treatment and greatly improves the outcome of patients. Individual therapy is strongly recommended.

Safety of Individual Medication of Ma Qian Zi (Semen Strychni) Based upon Assessment of Therapeutic Effects of Guo's Therapy Against Moderate Fluorosis of Bone

Objective: To assess the safety of individual medication of Guo's Ma Qian Decoction on the basis of effective treatment of fluorosis of bone with Guo's therapy. Methods: One hundred and fourteen cases of moderate fluorosis of bone were randomly divided into a treatment group (n=60) and a control group (n=54) between December 2007 and August 2009 by using the block randomized method and a central random system. At the same time of basic treatment, the patients in the treatment group were orally administrated with Guo's Ma Qian Decoction. The initial dose of Ma Qian Zi (Semen Strychni) was 0.4 g and increased by 0.05 g every two days, with the doses of other drugs unchanged, until the patient had "nux vomica response". For the patients with no "nux vomica response", the dosage was continued to increase and the maximum dosage was not more than 1.2 g/day. The control group was treated with decoction placebo. The changes of strychnine and brucine contents before and after processing and after decoction of Ma Qian Zi (Semen Strychni) were determined with reversed-phase high-performance liquid chromatography, which were controlled within ranges stipulated in the Pharmacopeia; Adverse events were analyzed; Blood strychnine and brucine contents in 10 cases who had taken the drugs were determined. Results: 1) Strychnine (2.125%) and brucine (1.425%) contents before processing of Ma Qian Zi and 1.88% and 1.31% after processing all conformed with the standards of strychnine (1.2-2.2%) and brucine (no less than 0.8%) stipulated in the Pharmacopeia. When the maximum dosage of Ma Qian Zi was 1.2 g/day, strychnine in the decoction was 11.17 mg and brucine was 7.44 mg, which all conformed with the maximum limited amount (strychnine 13.32 and brucine no less than 4.8 mg) stipulated in the Pharmacopeia. 2) Eight cases had "nux vomica response" in the treatment group and one case in the control group, with a significant difference between the two groups (P<0.05). 3) Altogether 18 cases had adverse events, with an incidence rate of 15.38% (8 cases) in the treatment group and 18.52% (10 cases) in the control group, with no difference between the two groups (P>0.05); Among them, 10 cases (8.77%) with the adverse event were not related with therapeutic drugs, with an incidence rate of 6.67% (4 cases) in the treatment and 11.11% (6 cases) in the control group, with no significant difference between the two groups (P>0.05). Seven cases had suspicious relative adverse events, the risk in the treatment group was 0.658 times of the control group, with no significant difference (P>0.05), and one case had the toxic reaction of nux-vomica seed. 4) Strychnine and brucine were unable to be detected in the blood in all points of time in the 10 cases who had taken the drugs, indicating that plasma strychnine and brucine contents were lower than the minimum detectable amount (10 ng), and accumulation of strychnine and brucine were not found in blood of the patient during and after administration for 8 weeks. Conclusion: The individual medication of Ma Qian Zi (Semen Strychni) in the Guo's therapy has a better safety.

Intermittent Oxygen Inhalation with Proper Frequency Improves Overall Health Conditions and Alleviates Symptoms in a Population at High Risk of Chronic Mountain Sickness with Severe Symptoms

Background： Oxygen inhalation therapy is essential for the treatment of patients with chronic mountain sickness （CMS）, but the efficacy of oxygen inhalation for populations at high risk of CMS remains unknown. This research investigated whether oxygen inhalation therapy benefits populations at high risk of CMS. Methods： A total of 296 local residents living at an altitude of 3658 m were included; of which these were 25 diagnosed cases of CMS, 8 cases dropped out of the study, and 263 cases were included in the analysis. The subjects were divided into high-risk （180 ≤ hemoglobin （Hb） 〈210 g/L, n = 161） and low-risk （Hb 〈180 g/L, n = 102） groups, and the cases in each group were divided into severe symptom （CMS score ≥6） and mild symptom （CMS score 0-5） subgroups. Severe symptomatic population of either high- or low-risk CMS was randomly assigned to no oxygen intake group （A group） or oxygen intake 7 times/week group （D group）; mild symptomatic population of either high- or low-risk CMS was randomly assigned to no oxygen intake group （A group）, oxygen intake 2 times/week group （B group）, and 4 times/week group （C group）. The courses for oxygen intake were all 30 days. The CMS symptoms, sleep quality, physiological biomarkers, biochemical markers, etc., were recorded on the day before oxygen intake, on the 15th and 30th days of oxygen intake, and on the 15th day after terminating oxygen intake therapy. Results： A total of 263 residents were finally included in the analysis. Among these high-altitude residents, CMS symptom scores decreased for oxygen inhalation methods B, C, and D at 15 and 30 days after oxygen intake and 15 days after termination, including dyspnea, palpitation, and headache index, compared to those before oxygen intake （B group： Z = 5.604, 5.092, 5.741; C group： Z = 4.155, 4.068, 4.809; D group： Z = 6.021, 6.196, 5.331, at the 3 time points respectively; all P 〈 0.05/3 vs. before intake）. However, dyspnea/palpitation （A group： Z = 5.003, 5.428, 5.493, both P 〈 0.05/3 vs. before intake） and headache （A group： Z = 4.263, 3.890, 4.040, both P 〈 0.05/3 vs. before intake） index decreased significantly also for oxygen inhalation method A at all the 3 time points. Cyanosis index decreased significantly 30 days after oxygen intake only in the group of participants administered the D method （Z= 2.701, P = 0.007）. Tinnitus index decreased significantly in group A and D at 15 days （A group： Z = 3.377, P = 0.001, D group： Z = 3.150, P - 0.002）, 30 days after oxygen intake （A group： Z = 2.836, P = 0.005, D group： Z = 5.963, P 〈 0.0001） and 15 days after termination （A group： Z- 2.734, P = 0.006, D group： Z - 4.049, P = 0.0001）, and decreased significantly in the group B and C at 15 days after termination （B group： Z = 2.611, P = 0.009; C group： Z = 3.302, P = 0.001）. In the population at high risk of CMS with severe symptoms, oxygen intake 7 times/weeksignificantly improved total symptom scores of severe symptoms at 15 days （4 [2, 5] vs. 5.5 [4, 7], Z = 2.890, P = 0.005） and 30 days （3 [1, 5] vs. 5.5 [2, 7], Z= 3.270, P = 0.001） after oxygen intake compared to no oxygen intake. In the population at high risk of CMS with mild symptoms, compared to no oxygen intake, oxygen intake 2 or 4 times/week did not improve the total symptom scores at 15 days （2 [1, 3], 3 [1, 4] vs. 3 [1.5, 5]; 2＂2 = 2.490, P= 0.288）, and at 30 days （2 [0, 4], 2 [1, 4.5] vs. 3 [2, 5];2＂2- 3.730, P = 0.155） after oxygen intake. In the population at low risk ofCMS, oxygen intake did not significantly change the white cell count and red cell count compared to no oxygen intake, neither in the severe symptomatic population nor in the mild symptomatic population. Conclusions： Intermittent oxygen inhalation with proper frequency might alleviate symptoms in residents at high altitude by improving their overall health conditions. Administration of oxygen inhalation therapy 2-4 times/week might not benefit populations at high risk of CMS with mild CMS symptoms while administration of therapy 7 times/week might benefit those with severe symptoms. Oxygen inhalation therapy is not recommended for low-risk CMS populations.