When conducting a literature review,medical authors typically search for relevant keywords in bibliographic databases or on search engines like Google.After selecting the most pertinent article based on the title’s r...When conducting a literature review,medical authors typically search for relevant keywords in bibliographic databases or on search engines like Google.After selecting the most pertinent article based on the title’s relevance and the abstract’s content,they download or purchase the article and cite it in their manuscript.Three major elements influence whether an article will be cited in future manuscripts:the keywords,the title,and the abstract.This indicates that these elements are the“key dissemination tools”for research papers.If these three elements are not determined judiciously by authors,it may adversely affect the manuscript’s retrievability,readability,and citation index,which can negatively impact both the author and the journal.In this article,we share our informed perspective on writing strategies to enhance the searchability and citation of medical articles.These strategies are adopted from the principles of search engine optimization,but they do not aim to cheat or manipulate the search engine.Instead,they adopt a reader-centric content writing methodology that targets well-researched keywords to the readers who are searching for them.Reputable journals,such as Nature and the British Medical Journal,emphasize“online searchability”in their author guidelines.We hope that this article will encourage medical authors to approach manuscript drafting from the perspective of“looking inside-out.”In other words,they should not only draft manuscripts around what they want to convey to fellow researchers but also integrate what the readers want to discover.It is a call-to-action to better understand and engage search engine algorithms,so they yield information in a desired and self-learning manner because the“Cloud”is the new stakeholder.展开更多
Apoptosis or programmed cell death (PCD) is an evolutionarily conserved cellular process that is essential for normal development and homeostasis of multicellular organisms. Defects in the apoptosis signaling result i...Apoptosis or programmed cell death (PCD) is an evolutionarily conserved cellular process that is essential for normal development and homeostasis of multicellular organisms. Defects in the apoptosis signaling result in many diseases including autoimmune diseases and cancer. The apoptosis signaling pathway was first described genetically in the nematode Caenorhabditis elegans which serves as a framework for the more complex apoptotic pathways that exist in mammals. In this review, we will discuss the apoptotic pathways that are emerging in mammals as elucidated by studies of gene-targeted mutant mice.展开更多
Objective: To investigate the pattern of palliative surgeries and associated costs in patients with metastatic melanoma in the USA. Methods: This was a retrospective claims-based study of patients identified using adm...Objective: To investigate the pattern of palliative surgeries and associated costs in patients with metastatic melanoma in the USA. Methods: This was a retrospective claims-based study of patients identified using administrative claims from MarketScan®?databases among patients with metastatic melanoma diagnosed between 2005 and 2011. Patient characteristics, patterns and cost of surgery, and length of hospital stay were evaluated. Results: Of the 2399 patients identified, 888 (37.0%) underwent at least one surgical procedure either in the outpatient or inpatient setting. The subgroup of patients who underwent surgery included significantly more patients with distant skin metastases compared to the subgroup who did not receive surgery;whereas significantly more patients in the non-surgery group had brain or bone metastases. Surgery performed in the outpatient setting was predominantly on the skin, whereas surgery on the brain was generally performed in the inpatient setting. The mean cost of the surgical procedures performed in the outpatient setting was $3393 (median: $1419) per procedure, which varied according to the location of the metastasis. For surgical procedures that were performed in the inpatient setting, the mean length of stay in hospital due to surgery was 4.4 (± 5.1) days, at a mean cost of $37,649 (median: $28,067) per hospitalization. Conclusions: Surgery is prevalent and costly in patients with metastatic melanoma.展开更多
Background: Monoclonal antibody treatments for metastatic colorectal cancer (mCRC) have distinct treatment-related safety profiles. This study aimed to elucidate the hospitalisation costs of adverse events (AEs) commo...Background: Monoclonal antibody treatments for metastatic colorectal cancer (mCRC) have distinct treatment-related safety profiles. This study aimed to elucidate the hospitalisation costs of adverse events (AEs) commonly associated with monoclonal antibodies when administered to patients with mCRC. Methods: This study extracted data for patients newly diagnosed with mCRC from a large US claims database from January 2005 to June 2008. The first distant metastasis diagnosis date was defined as the index date. Main outcomes were length of hospital stay (days) and hospitalisation costs (2010 US$) for AEs (identified by primary discharge diagnoses). All analyses are presented descriptively. Results: The study population (aged ≥18 years;n = 12,648) was balanced according to gender and was mainly aged 50 years or older (90.1%). Most patients had colon cancer (70.1%) as opposed to rectal cancer. Gastrointestinal (GI) perforation incurred the longest median length of stay (11.5 days) for hospitalisations, followed by wound-healing complications (7 days), arterial and venous thromboembolism (5.5 and 4 days, respectively), and congestive heart failure (4 days). The highest inpatient cost per event was for GI perforations (mean $66,224 and median $ 34,027), followed by arterial thromboembolism ($40,992 and $18,587), wound-healing complications ($36,440 and $21,163), interstitial lung disease ($26,705 and $19,111) and acute myocardial infarction ($22,395 and $15,223). Skin toxicity (mean $6475 and median $6110) and hypertension ($14,108 and $6047) were associated with relatively low costs. Conclusions: Hospital costs for monoclonal antibody treatment-related AEs in patients with mCRC vary greatly. This study provides source data for economic evaluations of head-to-head comparisons of monoclonal antibody treatments.展开更多
Background: Melanoma is a rare but serious skin cancer that is responsible for >90% of skin cancer-related deaths. This retrospective data analysis quantifies the direct cost of medical care by disease stage at dia...Background: Melanoma is a rare but serious skin cancer that is responsible for >90% of skin cancer-related deaths. This retrospective data analysis quantifies the direct cost of medical care by disease stage at diagnosis for patients with metastatic melanoma. Methods: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was queried for patients diagnosed between 2004-2009 with stage IIIB/C and stage IV (M1a, M1b, M1c) melanoma. The primary outcome was overall medical utilization and associated costs from diagnosis to death, the end of Medicare enrolment, or 12/31/2010. Results are stratified by disease stage at diagnosis and presented as per-patient per-month (PPPM) costs. Results: Of the 1263 patients meeting the study criteria (mean age: 75 years;64% male, 92% white, mean duration of follow up: 37.5 months), 66.6% were diagnosed at stage IIIB/C and 33.4% at stage IV. Cost of care increased with disease stage. Total PPPM costs ranged from $1966 for patients diagnosed with stage IIIB to $4585 among patients diagnosed with stage M1c. Outpatient costs accounted 48.9% of total medical costs among stage IIIB patients, and 38.7% of total medical costs for stage M1c patients. Inpatient costs accounted for 37.1% (stage M1b) - 40.9% (stage M1c) of total medical costs. Conclusions: Healthcare costs for treating patients with metastatic melanoma increase by disease stage. The cost of care was more than double among patients with late stage compared to those with early stage. Treatments demonstrating ability to prevent disease progression from early stage to late stage may confer an economic benefit among other clinical advantages.展开更多
BACKGROUND Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical manage...BACKGROUND Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown. AIM To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management. METHODS Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up. RESULTS Overall, 229 patients (males, 57.6%;mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity;the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%;emollients, 75.5%;both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low. CONCLUSION The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient’s quality of life appeared to be limited.展开更多
Urinary concentrations of 2:16-hydroxyestrone (2:16-OHE1) approximate concentrations of 2-OHE1 and 16α-OHE1 in breast tissue. As estrogens are purported to be involved in breast cancer development, the 2:16-OHE1 rati...Urinary concentrations of 2:16-hydroxyestrone (2:16-OHE1) approximate concentrations of 2-OHE1 and 16α-OHE1 in breast tissue. As estrogens are purported to be involved in breast cancer development, the 2:16-OHE1 ratio can provide an indication of estrogen metabolite exposure in the breast. With prior studies observing associations between urinary estrogen metabolites and dietary intakeof fruits, vegetables, and fiberascertained from food questionnaires, we examined associations between dietary factors ascertained through 3-day food records and urinary 2:16-OHE1 in191 pre-menopausal healthy women. Fruit consumption was positively associated with 2:16-OHE1 after adjustment for total energy, ethnicity, body mass index, parity, smoking history, and serum estradiol (p = 0.003). Fruit consumption was positively associated with 2-OHE1 concentrations (p = 0.006), but was not associated with 16α-OHE1 (p = 0.92). The Musaceae botanical grouping (comprised primarily of bananas) was positively associated with the 2:16-OHE1 ratio, and Rosaceae (comprised of citrus fruits) and Musaceae botanical groupings were positively associated with 2-OHE1 (but not 16α-OHE1) concentrations, after adjustment for confounders. Our data suggest that dietary fruit intakeis associated with urinary 2-OHE1 and the 2:16-OHE1 ratio and that breast tissue exposure to estrogen metabolites may thus be influenced-by diet.展开更多
To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites ca...To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors.Herein,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell mem-brane.EPI acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity cycle.The biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)depletion.The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive one.Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody.This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.展开更多
Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that s...Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups,high stability,great biocompatibility and desired dual-modality imaging results remains challenging.In this study,we used an amphiphilic block polymer from(ethylene glycol)methyl ether methacrylate(OEGMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)derivatives as a carrier to conjugate a MR contrast agent,Gd-DOTA,and a two-photon fluorophore with an aggregation-induced emission(AIE)effect,TPBP,to construct a MR/two-photon fluorescence dual-modality contrast agent,Gd-DOTA-TPBP.Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r_(1)value for Gd-DOTA-TPBP,revealing a great MR imaging resolution.The contrast agent specifically accumulated in the tumor region,allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging.Meanwhile,coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity,but also significantly enhanced its imaging performance in an aqueous phase.Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI.Since high-resolution,complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP,it has great potential in the early phase of disease diagnosis.展开更多
The authors regret the incorrect publication of corresponding authors for the article.The corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@126.com)and Kui Luo(luokui@scu.edu.cn),and the same should b...The authors regret the incorrect publication of corresponding authors for the article.The corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@126.com)and Kui Luo(luokui@scu.edu.cn),and the same should be updated in the supplementary file as well.展开更多
Computer-aided synthesis planning(CASP)integrates intuition of chemists and reliability of computers.As an in-between of unique creativities of human beings and unparalleled calculational capability of computers,CASP ...Computer-aided synthesis planning(CASP)integrates intuition of chemists and reliability of computers.As an in-between of unique creativities of human beings and unparalleled calculational capability of computers,CASP has become an important tool used in academic and industrial research.With explosion of novel chemical reactions,increasing of computer performance,and revolution of algorithms,CASP will play more significant roles in the synthetic chemistry field,inspiring novel and highly efficient syntheses of natural products and drug candidates.In this article,we review the progress in computational analysis of synthetic planning from rule-based programs(e.g.,LHASA and SECS)in the early stage to machine learning(e.g.,neural networks and seq2seq methods)in more recent years.展开更多
对于具有较高受试者个体间差异的药物进行生物等效性(BE)和生物类似性评价时,使用通常的双单侧检验(TOST)法既十分困难,甚至也不可能;除非不考虑伦理规范,而进行大样本的人体试验。因此,美国食品药品管理局(FDA)和欧盟药品管理局(EMA)...对于具有较高受试者个体间差异的药物进行生物等效性(BE)和生物类似性评价时,使用通常的双单侧检验(TOST)法既十分困难,甚至也不可能;除非不考虑伦理规范,而进行大样本的人体试验。因此,美国食品药品管理局(FDA)和欧盟药品管理局(EMA)等监管机构对高个体差异药品的生物等效性评价分别颁布了替代方法。这2个监管机构的替代方法依据相同的原理,但是关键细节略有不同。FDA建议当受试者个体间差异超过30%时,使用"标化均值生物等效性"(scaled-average BE,SABE)评价;该方式使用已有计算机软件通过线性转换来计算等效性的95%上限;并要求采用第2级标准评价:两产品间相关参数的几何均值之比的点评估(point estimate)在0.80到1.25之间。而EMA则建议采用"带扩展限度的平均生物等效性"(average BE with expanding limits,ABEL)进行高个体差异药品的评价;该方式与SABE方式相关,但可以使用简单的双单侧检验方法进行评估;EMA也要求采用相同的第,2级标准评价,且要求这2个标准仅适用于受试者个体间差异不超过50%的情形。这2个机构采用了不同的监管常数(等效性评价指标)。FDA建议的计算指标会使生物等效限不连续,且所需样本量大,并且在CV=30%附近有很高的I型误差。而EMA的评价指标不会产生这种不连续性,I型误差也很低。总之,EMA的评价方法更好。展开更多
Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs ...Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment.A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate,conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a(Ppa)with a branched glycopolymer.The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B,and PTX was simultaneously released to exert its therapeutic effect.The theranostic nanomedicine,branched glycopolymer-PTX-DOTA-Gd,had an extended circulation time,enhanced accumulation in tumors,and excellent biocompatibility with significantly reduced gadolinium ion(Gd3+)retention after 96 h post-injection.Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90%were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity.This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.展开更多
Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by ...Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.展开更多
Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics.However,direct administration of“naked”immunotherapeutic agents(such as nucleic aci...Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics.However,direct administration of“naked”immunotherapeutic agents(such as nucleic acids,cytokines,adjuvants or antigens without delivery vehicles)often results in:(1)an unsatisfactory efficacy due to suboptimal pharmacokinetics;(2)strong toxic and side effects due to low targeting(or off-target)efficiency.To overcome these shortcomings,a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects.Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties,as they could interact with immune system to stimulate an enhanced immune response.Their structures offer versatility in synthesizing multifunctional nanocomposites,which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues.This review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.展开更多
文摘When conducting a literature review,medical authors typically search for relevant keywords in bibliographic databases or on search engines like Google.After selecting the most pertinent article based on the title’s relevance and the abstract’s content,they download or purchase the article and cite it in their manuscript.Three major elements influence whether an article will be cited in future manuscripts:the keywords,the title,and the abstract.This indicates that these elements are the“key dissemination tools”for research papers.If these three elements are not determined judiciously by authors,it may adversely affect the manuscript’s retrievability,readability,and citation index,which can negatively impact both the author and the journal.In this article,we share our informed perspective on writing strategies to enhance the searchability and citation of medical articles.These strategies are adopted from the principles of search engine optimization,but they do not aim to cheat or manipulate the search engine.Instead,they adopt a reader-centric content writing methodology that targets well-researched keywords to the readers who are searching for them.Reputable journals,such as Nature and the British Medical Journal,emphasize“online searchability”in their author guidelines.We hope that this article will encourage medical authors to approach manuscript drafting from the perspective of“looking inside-out.”In other words,they should not only draft manuscripts around what they want to convey to fellow researchers but also integrate what the readers want to discover.It is a call-to-action to better understand and engage search engine algorithms,so they yield information in a desired and self-learning manner because the“Cloud”is the new stakeholder.
文摘Apoptosis or programmed cell death (PCD) is an evolutionarily conserved cellular process that is essential for normal development and homeostasis of multicellular organisms. Defects in the apoptosis signaling result in many diseases including autoimmune diseases and cancer. The apoptosis signaling pathway was first described genetically in the nematode Caenorhabditis elegans which serves as a framework for the more complex apoptotic pathways that exist in mammals. In this review, we will discuss the apoptotic pathways that are emerging in mammals as elucidated by studies of gene-targeted mutant mice.
文摘Objective: To investigate the pattern of palliative surgeries and associated costs in patients with metastatic melanoma in the USA. Methods: This was a retrospective claims-based study of patients identified using administrative claims from MarketScan®?databases among patients with metastatic melanoma diagnosed between 2005 and 2011. Patient characteristics, patterns and cost of surgery, and length of hospital stay were evaluated. Results: Of the 2399 patients identified, 888 (37.0%) underwent at least one surgical procedure either in the outpatient or inpatient setting. The subgroup of patients who underwent surgery included significantly more patients with distant skin metastases compared to the subgroup who did not receive surgery;whereas significantly more patients in the non-surgery group had brain or bone metastases. Surgery performed in the outpatient setting was predominantly on the skin, whereas surgery on the brain was generally performed in the inpatient setting. The mean cost of the surgical procedures performed in the outpatient setting was $3393 (median: $1419) per procedure, which varied according to the location of the metastasis. For surgical procedures that were performed in the inpatient setting, the mean length of stay in hospital due to surgery was 4.4 (± 5.1) days, at a mean cost of $37,649 (median: $28,067) per hospitalization. Conclusions: Surgery is prevalent and costly in patients with metastatic melanoma.
文摘Background: Monoclonal antibody treatments for metastatic colorectal cancer (mCRC) have distinct treatment-related safety profiles. This study aimed to elucidate the hospitalisation costs of adverse events (AEs) commonly associated with monoclonal antibodies when administered to patients with mCRC. Methods: This study extracted data for patients newly diagnosed with mCRC from a large US claims database from January 2005 to June 2008. The first distant metastasis diagnosis date was defined as the index date. Main outcomes were length of hospital stay (days) and hospitalisation costs (2010 US$) for AEs (identified by primary discharge diagnoses). All analyses are presented descriptively. Results: The study population (aged ≥18 years;n = 12,648) was balanced according to gender and was mainly aged 50 years or older (90.1%). Most patients had colon cancer (70.1%) as opposed to rectal cancer. Gastrointestinal (GI) perforation incurred the longest median length of stay (11.5 days) for hospitalisations, followed by wound-healing complications (7 days), arterial and venous thromboembolism (5.5 and 4 days, respectively), and congestive heart failure (4 days). The highest inpatient cost per event was for GI perforations (mean $66,224 and median $ 34,027), followed by arterial thromboembolism ($40,992 and $18,587), wound-healing complications ($36,440 and $21,163), interstitial lung disease ($26,705 and $19,111) and acute myocardial infarction ($22,395 and $15,223). Skin toxicity (mean $6475 and median $6110) and hypertension ($14,108 and $6047) were associated with relatively low costs. Conclusions: Hospital costs for monoclonal antibody treatment-related AEs in patients with mCRC vary greatly. This study provides source data for economic evaluations of head-to-head comparisons of monoclonal antibody treatments.
文摘Background: Melanoma is a rare but serious skin cancer that is responsible for >90% of skin cancer-related deaths. This retrospective data analysis quantifies the direct cost of medical care by disease stage at diagnosis for patients with metastatic melanoma. Methods: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was queried for patients diagnosed between 2004-2009 with stage IIIB/C and stage IV (M1a, M1b, M1c) melanoma. The primary outcome was overall medical utilization and associated costs from diagnosis to death, the end of Medicare enrolment, or 12/31/2010. Results are stratified by disease stage at diagnosis and presented as per-patient per-month (PPPM) costs. Results: Of the 1263 patients meeting the study criteria (mean age: 75 years;64% male, 92% white, mean duration of follow up: 37.5 months), 66.6% were diagnosed at stage IIIB/C and 33.4% at stage IV. Cost of care increased with disease stage. Total PPPM costs ranged from $1966 for patients diagnosed with stage IIIB to $4585 among patients diagnosed with stage M1c. Outpatient costs accounted 48.9% of total medical costs among stage IIIB patients, and 38.7% of total medical costs for stage M1c patients. Inpatient costs accounted for 37.1% (stage M1b) - 40.9% (stage M1c) of total medical costs. Conclusions: Healthcare costs for treating patients with metastatic melanoma increase by disease stage. The cost of care was more than double among patients with late stage compared to those with early stage. Treatments demonstrating ability to prevent disease progression from early stage to late stage may confer an economic benefit among other clinical advantages.
文摘BACKGROUND Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown. AIM To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management. METHODS Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up. RESULTS Overall, 229 patients (males, 57.6%;mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity;the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%;emollients, 75.5%;both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low. CONCLUSION The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient’s quality of life appeared to be limited.
文摘Urinary concentrations of 2:16-hydroxyestrone (2:16-OHE1) approximate concentrations of 2-OHE1 and 16α-OHE1 in breast tissue. As estrogens are purported to be involved in breast cancer development, the 2:16-OHE1 ratio can provide an indication of estrogen metabolite exposure in the breast. With prior studies observing associations between urinary estrogen metabolites and dietary intakeof fruits, vegetables, and fiberascertained from food questionnaires, we examined associations between dietary factors ascertained through 3-day food records and urinary 2:16-OHE1 in191 pre-menopausal healthy women. Fruit consumption was positively associated with 2:16-OHE1 after adjustment for total energy, ethnicity, body mass index, parity, smoking history, and serum estradiol (p = 0.003). Fruit consumption was positively associated with 2-OHE1 concentrations (p = 0.006), but was not associated with 16α-OHE1 (p = 0.92). The Musaceae botanical grouping (comprised primarily of bananas) was positively associated with the 2:16-OHE1 ratio, and Rosaceae (comprised of citrus fruits) and Musaceae botanical groupings were positively associated with 2-OHE1 (but not 16α-OHE1) concentrations, after adjustment for confounders. Our data suggest that dietary fruit intakeis associated with urinary 2-OHE1 and the 2:16-OHE1 ratio and that breast tissue exposure to estrogen metabolites may thus be influenced-by diet.
基金National Natural Science Foundation of China(52073193,51873120 and 81621003)1‧3‧5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013)。
文摘To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors.Herein,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell mem-brane.EPI acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity cycle.The biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)depletion.The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive one.Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody.This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.
基金supported by National Natural Science Foundation of China(52073193,51873120,81621003,51903173)1⋅3⋅5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013)+1 种基金Science and Technology Program of Sichuan province(2020YJ0231)China Postdoctoral Science Foundation(2021M692255).
文摘Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups,high stability,great biocompatibility and desired dual-modality imaging results remains challenging.In this study,we used an amphiphilic block polymer from(ethylene glycol)methyl ether methacrylate(OEGMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)derivatives as a carrier to conjugate a MR contrast agent,Gd-DOTA,and a two-photon fluorophore with an aggregation-induced emission(AIE)effect,TPBP,to construct a MR/two-photon fluorescence dual-modality contrast agent,Gd-DOTA-TPBP.Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r_(1)value for Gd-DOTA-TPBP,revealing a great MR imaging resolution.The contrast agent specifically accumulated in the tumor region,allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging.Meanwhile,coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity,but also significantly enhanced its imaging performance in an aqueous phase.Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI.Since high-resolution,complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP,it has great potential in the early phase of disease diagnosis.
文摘The authors regret the incorrect publication of corresponding authors for the article.The corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@126.com)and Kui Luo(luokui@scu.edu.cn),and the same should be updated in the supplementary file as well.
基金support from the NSFC of China(21925106)Sichuan University(2020SCUNL204)for Dr.Bo Liu and Zhuang Wang.Dr.Wenhan Zhang is not supported by any funding.
文摘Computer-aided synthesis planning(CASP)integrates intuition of chemists and reliability of computers.As an in-between of unique creativities of human beings and unparalleled calculational capability of computers,CASP has become an important tool used in academic and industrial research.With explosion of novel chemical reactions,increasing of computer performance,and revolution of algorithms,CASP will play more significant roles in the synthetic chemistry field,inspiring novel and highly efficient syntheses of natural products and drug candidates.In this article,we review the progress in computational analysis of synthetic planning from rule-based programs(e.g.,LHASA and SECS)in the early stage to machine learning(e.g.,neural networks and seq2seq methods)in more recent years.
文摘对于具有较高受试者个体间差异的药物进行生物等效性(BE)和生物类似性评价时,使用通常的双单侧检验(TOST)法既十分困难,甚至也不可能;除非不考虑伦理规范,而进行大样本的人体试验。因此,美国食品药品管理局(FDA)和欧盟药品管理局(EMA)等监管机构对高个体差异药品的生物等效性评价分别颁布了替代方法。这2个监管机构的替代方法依据相同的原理,但是关键细节略有不同。FDA建议当受试者个体间差异超过30%时,使用"标化均值生物等效性"(scaled-average BE,SABE)评价;该方式使用已有计算机软件通过线性转换来计算等效性的95%上限;并要求采用第2级标准评价:两产品间相关参数的几何均值之比的点评估(point estimate)在0.80到1.25之间。而EMA则建议采用"带扩展限度的平均生物等效性"(average BE with expanding limits,ABEL)进行高个体差异药品的评价;该方式与SABE方式相关,但可以使用简单的双单侧检验方法进行评估;EMA也要求采用相同的第,2级标准评价,且要求这2个标准仅适用于受试者个体间差异不超过50%的情形。这2个机构采用了不同的监管常数(等效性评价指标)。FDA建议的计算指标会使生物等效限不连续,且所需样本量大,并且在CV=30%附近有很高的I型误差。而EMA的评价指标不会产生这种不连续性,I型误差也很低。总之,EMA的评价方法更好。
基金financially supported by the National Natural Science Foundation of China(Nos.51873120,51673127,and 81621003)Department of Science and Technology of Sichuan Province(Nos.2018JY0574,2017SZ0006,18GJHZ0139,and 2018HH0006,China)1·3·5 Research Funds in West China Hospital of Sichuan University(ZYGD18028,China)
文摘Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment.A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate,conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a(Ppa)with a branched glycopolymer.The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B,and PTX was simultaneously released to exert its therapeutic effect.The theranostic nanomedicine,branched glycopolymer-PTX-DOTA-Gd,had an extended circulation time,enhanced accumulation in tumors,and excellent biocompatibility with significantly reduced gadolinium ion(Gd3+)retention after 96 h post-injection.Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90%were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity.This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.
基金financially supported by the National Natural Science Foundation of China(82073790,51873120,51673127,and 81621003)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University,China(ZYJC21013,ZYGD18028)。
文摘Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.
基金This work was supported by the National Natural Science Foundation of China(51873120,51673127,81621003)National Science and Technology Major Project of China(2017ZX09304023)+1 种基金Ruilong Sheng,Helena Tomas and Joao Rodrigues appreciate the support from Fundaçao para a Ciencia e a Tecnologia(Base Fund UIDB/00674/2020,CQM,Portuguese Government Funds)ARDITI-Agencia Regional para o Desenvolvimento da Investigaçao Tecnologia e Inovaçao through the project M1420-01-0145-FEDER-000005-Centro de Química da Madeira-CQM+(Madeira 14-20 Program)and ARDITI-2017-ISG-003.
文摘Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics.However,direct administration of“naked”immunotherapeutic agents(such as nucleic acids,cytokines,adjuvants or antigens without delivery vehicles)often results in:(1)an unsatisfactory efficacy due to suboptimal pharmacokinetics;(2)strong toxic and side effects due to low targeting(or off-target)efficiency.To overcome these shortcomings,a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects.Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties,as they could interact with immune system to stimulate an enhanced immune response.Their structures offer versatility in synthesizing multifunctional nanocomposites,which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues.This review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.