In silico designed mRNA vaccines targeting CA-125 neoantigen in breast and ovarian cancer

Somatic mutation-derived neoantigens are associated with patient survival in breast and ovarian cancer. These neoantigens are targets for cancer, as shown by the implementation of neoepitope peptides as cancer vaccines. The success of cost-effective multi-epitope mRNA vaccines against SARS-Cov-2 in the pandemic established a model for reverse vaccinology. In this study, we aimed to develop an in silico pipeline designing an mRNA vaccine of the CA-125 neoantigen against breast and ovarian cancer, respectively. Using immuno-bioinformatics tools, we predicted cytotoxic CD8⁺ T cell epitopes based on somatic mutation-driven neoantigens of CA-125 in breast or ovarian cancer, constructed a self-adjuvant mRNA vaccine with CD40L and MHC-I -targeting domain to enhance cross-presentation of neoepitopes by dendritic cells. With an in silico ImmSim algorithm, we estimated the immune responses post-immunization, showing IFN-γ and CD8⁺ T cell response. The strategy described in this study may be scaled up and implemented to design precision multi-epitope mRNA vaccines by targeting multiple neoantigens.     

Relationship of communication and information measures to colorectal cancer screening utilization: results from HINTS

Utilization of colorectal cancer screening tests is suboptimal. Knowledge of colorectal cancer screening has been associated with completion of screening. Thus, increasing awareness of colorectal cancer screening may lead to significant improvements in screening rates. We assessed for the association among provider-patient interaction, information-seeking patterns, sources of information, trust in cancer information, and Internet usage on colorectal cancer screening behavior using data obtained by the Health Information National Trends Survey (HINTS). From a cohort of 2,670 respondents greater than 50 years of age, we found that they (1) desired cancer information from personalized reading materials, meeting in person with a health care professional, and published materials; and (2) had great trust of information from their provider. Having trust in cancer information from the doctor or other health care professional was most predictive (OR 2.08, 95% CI 1.49-2.94) of being up to date. Other predictive factors include having a desire for cancer information from personalized reading materials (OR 1.56, 95% CI 1.24-1.95) and using the Internet from home (OR 1.32, 95% CI 1.04-1.67). We conclude that personalized communications from a health care provider are desired and trusted. Another promising information delivery approach is the Internet. Dedicated efforts using these approaches for information exchange may be most beneficial toward increasing utilization of colorectal cancer screening.     

The art of casting nets: fishing for the prize of personalized cancer prevention

Now, more than ever, there is great need for personalized cancer prevention. We define personalized cancer prevention as a strategy that will enable each person to reduce his or her risk for lethal cancer by matching the dose, duration, and timing of an intervention with their own cancer risk profile. Most research studies provide us with data on the average person. But who is the average person anyway? The central tenet of personalized cancer prevention is that average is overrated. In this article, we frame what are the major obstacles to developing personalized cancer-reducing interventions: the lack of validated, non-invasive stratifiers of risk; the U-shaped dose response between cancer-fighting nutrients (e.g., selenium) and DNA damage, meaning that more of a good thing is not necessarily a good thing; the relatively brief duration of interventions evaluated in human prevention trials; the challenge of finding populations in which the impact of early life interventions on the incidence of cancers affecting older adults can be studied; and the interindividual differences in gene expression that may influence a person's response to a particular nutrient. Moreover, we contend that those who study personalized cancer prevention will need a unique constellation of expertise, including an understanding of cancer and aging, a passion for prevention, and proven health communication skills. We propose that becoming cross-trained in cancer and aging and taking more responsibility for communicating health-related research to the public in the proper context are two of the most important ways scientists can move us all closer to the goal of personalized cancer prevention. Every fisherman knows that where he casts his net determines his catch. Now, we ask: When it comes to solving the cancer problem, where should we be casting our nets?     

宫颈癌治疗性疫苗的临床研究现状

人乳头瘤状病毒(human papillomavirus,HPV)是宫颈癌的主要致病因子,也是研制宫颈癌防治性疫苗的理想靶点。虽然现在针对HPV感染的宫颈癌预防性疫苗已成功上市,但是对于急需的治疗型疫苗的研发还在进行中。目前有多种类型的治疗性疫苗已用于临床前期及临床试验,并显示出很好的治疗效果。本文从活载体疫苗、多肽/蛋白疫苗、DNA疫苗和DC疫苗几个方面综述了目前国内外宫颈癌治疗性疫苗的研究现状及进展,特别是进入临床阶段的疫苗,从而为治疗性疫苗的研究提供参考。     

Syngeneic B16-F1 cells are more efficient than allogeneic Cloudman cells as antigen source in DC-based vaccination in the B16-F1 murine melanoma model

A major obstacle to obtaining relevant results in cancer vaccination has been the lack of identification of immunogenic antigens. Dendritic cell (DC)-based cancer vaccines used preventively may afford protection against tumor inoculation, but the effect of antigen choice on anti-tumor protection is not clear. When using irradiated syngeneic tumor cells to load DCs, tumor self-antigens are provided, including tumor-associated antigens (TAAs) and neoantigens generated by tumor mutations. On the other hand, allogeneic tumor cells could only supply shared TAAs. To assess the advantages of each source in protective vaccination, we analyzed in C57BL/6 mice the effect of loading DCs with irradiated syngeneic B16-F1 or allogeneic Cloudman melanoma cells; both cell lines were characterized by whole exome sequencing and RNAseq. Tumor cell components from the two irradiated cell lines were efficiently internalized by DCs, and transported to MHC-class II positive tubulovesicular compartments (MIICs). DCs loaded with allogeneic irradiated Cloudman cells (DC-ApoNec_ALLO) induced a partially effective anti-melanoma protection, although Cloudman and B16-F1 cells share the expression of melanocyte differentiation antigens (MDAs), cancer-testis antigens (CTAs) and other TAAs. DCs loaded with syngeneic B16-F1 cells (DC-ApoNec_SYN) established a more potent and long-lasting protection and induced a humoral anti-B16F1 response, thus suggesting that neoepitopes are needed for inducing long-lasting protection.     

宫颈癌合并糖尿病患者围手术期护理分析

目的 探讨宫颈癌合并糖尿病患者围手术期护理措施及效果。 方法 将2012年7月至2014年7月因宫颈癌合并糖尿病住院治疗的80例患者随机分为观察组和对照组,对照组给予宫颈癌合并糖尿病常规护理,观察组在此基础上实施针对性护理,评价2组护理干预后1个月生活质量改善情况、护理满意度及并发症发生情况。 结果 观察组5项ADL指标得分均低于对照组(P<0.01)。观察组护理满意率95.0%,高于对照组的82.5%,差异有统计学意义(P<0.05);并发症发生率低于对照组,差异有统计学意义(P<0.05)。 结论 在常规护理基础上,配合针对性护理干预有助于显著改善宫颈癌合并糖尿病患者临床症状,提高生活质量,减少不良反应发生。     

Immunity to Trop-1, a newly identified breast cancer antigen, inhibits the growth of breast cancer in mice

This study describes the immunotherapeutic properties of vaccines that encode tumor-associated calcium signal transducer-1 (Trop-1), a newly identified breast cancer antigen, in mice with breast cancer. Previously we found that Trop-1 was over-expressed in cellular breast cancer vaccines that were highly enriched for cells that induced therapeutic CTL-mediated immune responses in mice with breast cancer, as compared with non-enriched vaccines. In this study, to determine if the expression of Trop-1 by cells in the enriched vaccine was responsible for its therapeutic benefits, an expression plasmid that specified the Trop-1 gene was transfected into the LM fibroblast cells, which was then used as a vaccine. To augment their immunogenic properties, the fibroblasts were genetically modified before Trop-1 DNA-transfer to secrete IL-2 and to express allogeneic MHC class I H-2K(b)-determinants. Mice with established breast cancer treated solely by immunization with fibroblasts modified to express Trop-1 developed CD8(+) cell-mediated immunity to the breast cancer cells. The immunity was sufficient to prolong the survival of mice with established breast cancer. In some instances, the immunity was sufficient to result in rejection of the tumor; the mice remained tumor free more than 60 days.     

HPV vaccines to prevent cervical cancer and genital warts: an update

Cervical cancer is an important public health problem worldwide, and especially in developing countries. The link between cervical cancer and oncogenic human papillomavirus (HPV) infection has been clearly established. Furthermore, non-oncogenic HPV are responsible for the majority of genital warts. Two prophylactic HPV vaccines are available, which have the potential of considerably reducing HPV-related morbidity and mortality. Both vaccines are based on virus-like particles of the L1 capsid protein, and are highly efficacious and immunogenic if given before exposure to HPV, i.e. to adolescent girls between 9 and 13 years of age in a three-dose schedule. This review describes the immunology of natural HPV infections and the immune response evoked through vaccination. The current duration of protection is 8.4 years with the bivalent vaccine (HPV16/18) and 5 years with the quadrivalent vaccine (HPV6/11/16/18). Research is on-going to evaluate the efficacy of the current vaccines in a two-dose schedule, as compared to the recommended three-dose schedule. To increase the protection, the development and testing of a nine-valent prophylactic HPV vaccine (HPV6/11/16/18/31/33/45/52/58) is being undertaken. Research is also directed towards therapeutic vaccines and the development of a prophylactic L2 vaccine.     

Toward cervical cancer prevention: strategies employed in the development of HPV vaccines

An HPV persistent infection is doubtless the main factor involved in cervical cancer development. It is clear that the majority of HPV infections are self-limited and not all high-risk HPV infections are destined to progress to a higher grade lesion. Due to viral mechanisms that evade the immune system, in some cases the immune response against HPV is not as effective, allowing the establishment of persistent infections. The promise of a vaccine that can avoid HPV infections and therefore decrease cervical cancer incidence, has been motive of great interest and enthusiasm on the search of different strategies for obtaining an effective vaccine. At present, several prophylactic vaccines have been developed based in virus like particles (VLPs) produced with L1 viral proteins. Results of these vaccines applied to women between 16 and 23 years old show high tolerability and immunogenicity with higher antibody titers than those seen in an HPV natural infection. Even these vaccines can not wholly prevent infections caused by HPV types included in the vaccine design; its efficacy has been demonstrated for their ability to eliminate HPV persistent infections and to prevent the development of cervical intraepithelial neoplasia. These vaccines are currently in phase III of clinical trials, whose results will determine its impact in the general population. Therapeutic vaccines are focused in the elimination of established cervical lesions; nevertheless their efficacy has not been proved for clinical use.     

Periarteritis nodosa associated with lung cancer. A new observation

The cases of vasculitis associated to malignant tumour are uncommon, their course which is often parallel suggests a direct link between them. We report the observation of periarteritis nodosa associated with a lung cancer discovered in the following of vasculitis; whereas the course is favorable in 83 years old man without particular history. The frequency of neoplasia with vasculitis is estimated between 3 and 8%, and periarteritis nodosa can't be a paraneoplastic syndrome. Lung and colic tumours are the most frequent reported of the solid tumours. The delay of appearance of vasculitis varies from 25 months before to 9 months after cancer diagnosis. There are many factors, either some treatment, the neoantigens involve the formation of immune complexes, lymphokines and some vasoactive substances.     

癌症患者疫苗接种研究进展

癌症患者因恶性肿瘤本身或免疫抑制治疗而导致患疫苗可预防疾病的风险增加,其接种疫苗的种类、时机、剂量甚至免疫程序可能与正常人有所差别。目前国际上普遍推荐癌症患者接种灭活疫苗,而不提倡接种减毒活疫苗;应避免在免疫抑制治疗期间接种疫苗;推荐接种双倍剂量的乙型肝炎疫苗;推荐每年接种两针次灭活流感疫苗。本文旨在对国外癌症患者疫苗接种的临床试验进行总结,为我国制定和推行癌症患者的免疫接种提供借鉴。     

Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control

Universal deployment of organized or opportunistic screening with Pap cytology in high and middle income countries has been the primary reason for the substantial reductions in cervical cancer morbidity and mortality during the last 50 years. However, in many low income countries Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Cervical cancer thus remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. The fact that infection with certain human papillomavirus (HPV) types is now recognized as a necessary cause of this disease has led to new research fronts on the prevention of cervical cancer. Recent research on the safety and efficacy of candidate prophylactic vaccines against HPV have shown very promising results with nearly 100% efficacy in preventing the development of persistent infections and cervical precancerous lesions. Ongoing clinical studies are expected to provide further evidence of efficacy and will form the basis for licensing of candidate vaccines by the major pharmaceutical companies within 3-6 years. Although the future seems bright on the HPV vaccine front policy makers are strongly cautioned to avoid scaling back cervical cancer screening. It will take many years before we can rationally develop cervical cancer screening strategies that will be cost-effective for the proper surveillance of women protected by HPV vaccination.     

乳腺癌手术期患者个性化心理护理研究

目的：探讨分析个性化心理护理对乳腺癌手术期患者的影响。方法挑选2012年4月-2012年12月这一时间段内，于我院进行乳腺癌手术的患者80例，对其采取个性化心理护理，综合对比护理前后患者的焦虑、抑郁程度，进行护理有效性评估。结果于护理干预前，乳腺癌手术患者焦虑评分为（58.32±9.02）分，抑郁评分为（55.63±8.10）分，干预后依次为（51.55±5.68）分、（48.62±6.72）分，差异具有显著统计学意义（P＜0.05）；护理干预后患者社会活动、体能、心理健康、精神影响、社会活动、精力、体能影响等评分较干预前显著提高，差异具有显著统计学意义（P＜0.05）。结论个性化护理能有效减少乳腺癌手术期患者的负面心理，提升其治疗信心与生活质量，值得我们广泛应用。     

Vaccination against human papillomavirus for the prevention of cervical cancer

Persistent infections with high-risk Human papillomavirus (HPV) can lead to cervical cancer. This fact could imply that vaccination against HPV could prevent this disease. Such vaccines could be aimed at the prevention of HPV infections or the treatment of infections, cervical intraepithelial neoplasia (CIN) and cervical cancer. There are two prophylactic candidate vaccines against the high risk HPV types 16 and 18, which appear to be safe and effective in preventing incidental and persistent HPV infections. Phase III studies should reveal whether these vaccines will also have long-term effects by preventing the development of CIN and eventually cervical cancer. The introduction of such an HPV vaccine in the Netherlands, its cost-effectiveness and introduction into the existing national vaccination programmes needs to be studied. The vaccination of girls before they become sexually active seems to be the most effective approach, although older women can also profit from prophylactic vaccination. The current community-based screening, possibly complemented by an HPV test, needs to be continued to identify and treat presently HPV-infected women. In a population with an existing community-based screening program for cervical cancer, a vaccine preventing persisting infection with high-risk HPV will further reduce the incidence of HPV-related cervical cancer.     

Therapeutic vaccines against melanoma and colorectal cancer

Our overall strategy is to develop multivalent recombinant vaccines capable of eliciting broad immune responses in patients with malignant melanoma or colorectal cancer. We report herein results from initial studies conducted in cancer patients to evaluate the effect of intratumoral administration of recombinant canarypox viruses carrying cytokine genes. Our current focus is on the induction of tumor-specific T-cell responses using a prime/boost immunization schedule with a unique vector system derived from the canary pox virus called ALVAC, in which we incorporate genes encoding Tumor Associated Antigens (TAAs) of interest. Clinical studies in colorectal cancer evaluating an ALVAC CEA candidate vaccine have shown that this approach is safe and can induce tumor-specific T cell responses. Additional clinical studies evaluating candidate vaccines against melanoma and colorectal cancer, targeting either the gp100, Mage 1, Mage 3 or p53 molecules are ongoing.     

Cell based cancer vaccines: regulatory and commercial development

There is both clinical and regulatory drive to expedite development of safe, efficacious cancer therapies. Stimulation of the patients immune system through vaccination with tumour cells has long been at the vanguard of cancer therapeutic vaccines, and several have been demonstrated to be safe and to have efficacy in early clinical trials for a range of cancers including melanoma, renal cell carcinoma, prostate and colorectal cancers. A number of development-stage vaccines and strategies are currently being tested, utilising either autologous or allogeneic tumour cells, which may also have been ex vivo manipulated (e.g. cytokine transfected cells). It seems likely that clinical trial success, and hence patient benefit, could be improved through better patient identification, possibly by the discovery and use of novel immune response biomarkers. In this review, we aim to summarise the state of tumour cell vaccines in commercial development and to explore not only the difficulties of determining efficacy, but also the production challenges faced when developing a vaccine from proof of principle to pivotal phase III trials.     

A dynamic model for the risk of bladder cancer progression

We propose a multistate modeling approach to describe the observed evolution of patients diagnosed with non-muscle-invasive bladder cancer. On the basis of data from the Spanish Bladder Cancer/EPICURO study, we adjust a multistate model taking into account the disease-related events of interest (recurrence, progression, and disease-related deaths) as well as competing deaths due to other causes. We then develop a dynamic predictive process for bladder cancer progression, which allows the risk of a patient to be updated whenever new information of his or her evolution is available. By using specific measures of prospective accuracy in the presence of competing risks, the proposed dynamic model has shown to improve prediction accuracy and provides a more personalized management of bladder patients.     

Chapter 30: HPV vaccines and screening in the prevention of cervical cancer; conclusions from a 2006 workshop of international experts

The finding that cervical cancer only occurs in women infected with specific, "high-risk" types of the human papillomavirus (HPV) has led to the development of novel, non-cytology-based cervical cancer prevention strategies. We now have sensitive molecular methods for detecting HPV that dramatically improve our ability to detect high-grade cervical cancer precursor lesions. Perhaps more importantly, prophylactic HPV vaccines have been developed that are protective against cervical cancer precursors caused by HPV 16 and 18. In the Spring of 2006, over 100 experts in HPV, cervical cancer screening, and vaccination worked together to define how best to incorporate HPV DNA testing and the HPV vaccines into cervical cancer prevention efforts. In this summary, we summarize the opinions of this expert group on how these advances can be introduced to provide the maximum benefit to women and to reduce the global burden of cervical cancer.     

Travel vaccines are strongly associated to reduced mortality in prostate cancer patients - a real effect or residual confounding?

Repurposing of existing drugs and vaccines for diseases that they were not originally intended for is a promising research field. Recently there has been evidence that oral cholera vaccine might be used in the treatment of inflammatory disease and some common cancers. Specifically, Ji et al showed that the administration of cholera vaccine after a prostate cancer diagnosis reduced prostate cancer specific mortality rates by almost 50%. In a cohort of men from Stockholm, Sweden, with more detailed cancer data and a higher coverage of exposure to vaccine, we replicated these findings using a marginal structural Cox model. We showed that administration of cholera vaccine after prostate cancer diagnosis is associated with a significant reduction in mortality (HR 0.46, 95% CI 0.31–0.69, p-value 0.0001) even after adjusting for all known confounders. However, the same effect (or even stronger) could be seen for several other traveling vaccines and malaria prophylaxis. Therefore, we conclude that this effect is most likely due to a healthy traveler bias and is an example of residual confounding.     

Cervical cancer screening following prophylactic human papillomavirus vaccination

The recognition that infection with certain human papillomavirus (HPV) types is a necessary cause of cervical cancer has opened new fronts for the prevention of this disease. Primary prevention is now possible via immunization with highly efficacious HPV vaccines and secondary prevention has gained impetus with the advent of sensitive HPV DNA testing to improve traditional Pap cytology screening programs. Although universal vaccination of teenagers and young women is a desirable policy cost remains a key obstacle. To achieve cost-effective reductions in the burden of cervical cancer prevention initiatives must consider screening and immunization as integrated and organized approaches that take advantage of HPV testing as primary screening test followed by triage with Pap cytology. This strategy has the added benefit of providing epidemiological surveillance of vaccinated populations.