抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

A genetic model for colorectal tumorigenesis

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.

Genetic alterations during colorectal-tumor development.

https://bic.berkeley.edu/sites/default/files/Rossi_09_TMS%20safety%20review.pdf

Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research

The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.

http://www.protocol-online.org/forums/uploads/monthly_09_2010/post-8165-008503000%201284677034.ipb

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

✓ The 1.9-µ wavelength component of a 1.9/1.06-µ two-wavelength laser with near-continuous wave properties was tested for its potential use in neurosurgery. The 1.9-µ wavelength has tissue-ablative capabilities, while the 1.06-µ wavelength (Nd:YAG) is suitable for achieving hemostasis. The advantages of the 1.9-µ wavelength over the CO2 laser include its ability to transmit through silica fiberoptic delivery systems and its deeper penetration in water (approximately 100 µ, a depth 10 times greater than for the CO2 laser), which is compatible with irrigation during ablation. To test the effectiveness of the laser, bilateral craniotomies were performed in anesthetized rats immobilized in a stereotactic frame. Under an operating microscope, lesions were made on the cortex by delivering the 1.9-µ laser beam through a 400-µ fiber at an average power of 1 W over a range of fluences. Subjective intraoperative observations were notable for minimal bleeding, absence of charring when the tissue was irrigated with a...

A new 1.9-µ wavelength laser for neurosurgery

[Gene therapy for brain tumors: experimental treatment of malignant brain tumors using recombinant herpes simplex virus type 1 (series 7)].

Lymphangioleiomyomatosis (LAM) is a rare pulmonary condition often presenting with spontaneous pneumothorax. Imaging or biopsy confirm the diagnosis. Published case reports describe the anesthetic management of patients with LAM undergoing brief procedures. No reports describe the anesthetic management for lengthy neurosurgical procedures. We describe anesthetic management for craniotomy in a patient with LAM. Clinical Features. A woman presented with 2 spontaneous left pneumothoraces. She received a diagnosis of LAM by imaging. She did well after pleurodesis. Hearing loss and tinnitus led to brain imaging demonstrating a large left cerebello-pontine angle mass. She presented for elective craniotomy to remove the mass while preserving cranial nerve function. Our technique for general endotracheal anesthesia aimed to reduce the likelihood of another pneumothorax while providing good surgical conditions and permitting neuromonitoring. Conclusion. We demonstrate the successful anesthetic management of a patient with LAM undergoing a lengthy suboccipital craniotomy for a posterior fossa mass.

/pdf/anesthesia-for-suboccipital-craniotomy-in-a-patient-with-1caj1cx9q6.pdf

Anesthesia for Suboccipital Craniotomy in a Patient with Lymphangioleiomyomatosis: A Case Report

Glioblastoma, the most common primary brain tumor in adults, is invariably fatal despite all current therapies, with a median survival of about 15 months. Glioblastoma contains cancer stem cells or tumor-initiating cells, a subpopulation of cancer cells that are thought to be important in tumor initiation, progression, heterogeneity, recurrence and resistance to therapy, and thus likely critical targets for therapy. We used a mouse syngeneic glioblastoma stem cell (GSC) tumor model with 005 GSCs, isolated from activated H-Ras and Akt induced, Tp53+/- gliomas in C57Bl/6 mice, which recapitulates the hallmarks of human glioblastoma. Immunovirotherapy takes advantage of the natural inflammatory responses to virus infection and oncolytic virus-induced cancer cell death to drive antitumor immunity. Oncolytic herpes simplex viruses (oHSVs) are genetically-engineered to selectively replicate in cancer cells without harming normal tissue. In this study, we test G47∆-mIL12, an oHSV expressing murine IL-12, a critical cytokine involved in adaptive and innate immune responses as well as anti-angiogenesis. Immune checkpoints, such as co-inhibitory molecules like CTLA-4 and PD-1 with its ligand PD-L1 play a critical role in regulating immune responses and suppressing antitumor immune effector cells. PD-1 and CTLA-4 are expressed predominantly on T-cells, while PD-L1 is also expressed on endothelial and tumor cells. Blocking antibodies to these molecules have been shown to be very effective at reversing tumor-induced immunosuppression. Therefore, we hypothesized that an IL-12 expressing oHSV, which induces antitumor immune responses, should synergize with checkpoint inhibitor antibodies in inhibiting glioblastoma growth. Mouse 005 GSCs are highly tumorigenic and relatively non-immunogenic, lacking MHC1 expression, with PD-L1 only expressed on a minority of 005 GSCs in vitro. Both MHC1 and PD-L1 can be induced by IFN-γ. Mice with established orthotopic 005 GSC-derived tumors were treated with a single intratumoral injection of G47∆-mIL12 followed by systemic administration of anti-mPD-1, anti-mPD-L1, anti-mCTLA-4, or isotype control antibodies. Single treatments significantly, but modestly, improved survival compared to mock treatment. The combination of G47∆-mIL12 with either of the three checkpoint inhibitors further extended survival. However, the combination of G47∆-mIL12 with 2 checkpoint inhibitors is able to ‘cure’ mice of 005 brain tumors and protect them from tumor rechallenge. This is associated with a large increase in M1-like macrophages and T effector cells and decrease in T regulatory cells. In this representative glioblastoma stem cell model, the combination of oHSV, local IL12 expression, and 2 systemic checkpoint inhibitors was necessary to eliminate established tumors. Citation Format: Dipongkor Saha, Robert Martuza, Samuel Rabkin. Immunovirotherapy in combination with immune checkpoint inhibitors for treating glioblastoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B116.

Robert L. Martuza

Papers

A new 1.9-µ wavelength laser for neurosurgery

[Gene therapy for brain tumors: experimental treatment of malignant brain tumors using recombinant herpes simplex virus type 1 (series 7)].

Anesthesia for Suboccipital Craniotomy in a Patient with Lymphangioleiomyomatosis: A Case Report

Abstract B116: Immunovirotherapy in combination with immune checkpoint inhibitors for treating glioblastoma

Erratum: Therapeutic efficacy of G207 in a novel peripheral nerve sheath tumor model (Experimental Neurology (2001) 169:1 (64-71))