Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Impairments in the perception of odor-induced tastes and their relationship to impairments in taste perception

Certain odors have tastelike qualities when sniffed. To the extent that these qualities are akin to real taste experiences, impairment in perception of odor-induced tastes should be accompanied by taste impairment, and vice versa. Twelve patients were selected with possible odor-induced taste impairments or general taste impairments via a screening test, along with a further 6 patients with a probable taste impairment (insular lesion). These 18 patients, along with 19 normal controls, completed a battery of odor, taste, visual control, and neuropsychological tests to assess impairments in odor-induced taste perception and general taste perception. Four patients had an odor-induced taste impairment and were also impaired on taste perception. A further analysis, using regression on the whole sample, indicated that taste impairments were associated with odor-induced taste abnormalities independent of other predictors. This pattern also held for the patient group alone. The insular patients also exhibited both taste and odor-induced taste impairments. This study is the first to demonstrate a relationship between impaired taste perception and the perception of odor-induced tastes and suggests that both may rely on certain common neural substrates.15 page(s

Condyloma lata mimicking vulvar carcinoma in an immunocompromised patient: A case report

Background: Syphilis is a sexually transmitted infection with increasing incidence in the United States. Presentations of syphilis vary widely and can be easily mistaken for other diagnoses, including cancer, especially in atypical cases. Case description: At her delivery after no prenatal care, a 35-year-old woman was found to have exophytic vulvar and perianal lesions, inguinal lymphadenopathy, and a new diagnosis of HIV, with a strong clinical concern for vulvar and/or anal carcinoma. She was subsequently diagnosed with presumed late latent syphilis and began weekly intramuscular penicillin G benzathine treatment. CT imaging demonstrated a perineal plaque-like area with bilateral inguinal, external iliac and retroperitoneal lymphadenopathy. She was seen in gynecologic oncology clinic one week after her initial presentation with notable improvement in the vulvar lesions, raising suspicion for condyloma lata rather than invasive or preinvasive disease on the vulva, however concern remained for dysplasia in the perianal lesion. Another week later, she underwent an exam under anesthesia with vulvar and perianal biopsies revealing chronic inflammation and granulomatous change without evidence of malignancy or dysplasia. At the four week post operative visit, there was almost complete resolution of the lesions. Conclusion: Syphilis should be considered in the differential diagnosis of atypical vulvar lesions

Testing the importance of the Medial Temporal Lobes in human interoception : does it matter if there is a memory component to the task?

Interoception is the ability to consciously perceive internal bodily states. Neuroimaging suggests that the insula (IC) and anterior cingulate cortex (ACC) mediate interoception, while studies involving patients/animals with brain lesions suggest the medial temporal lobe (MTL) is particularly important. One reason for these contrasting conclusions may lie in the types of interoceptive task used by these different approaches. Some tasks probably require integration of current physiological state with mnemonic information (e.g., how much one last ate), and these may be especially reliant upon MTL processing. We compared one task that probably requires integration - a water load task - with one that likely does not - a heart-rate tracking task - in two individuals with selective MTL damage (and with intact IC and ACC). A group of matched healthy individuals served as controls. The main finding was that individuals with MTL damage, relative to controls, were equally and significantly impaired on both types of interoception task. This suggests that MTL structures are involved in mediating interoception even when using a task (heart rate tracking) that does not seemingly require memory and that in neuroimaging studies activates the IC and ACC. The reasons for this apparent inconsistency with neuroimaging findings and the functional role of the MTL in interoception are discussed.9 page(s