Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8⁺ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8⁺ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.     

有症状门诊病人深静脉血栓形成的诊断,临床评价和D-二聚体分析可能减少对影像学诊断的需要

深静脉血栓形成(DVT)的年发病率为48-182／10万,一般估计为1／1000。DVT病死率为1%-5%,发病率和病死率与年龄密切相关。慢性疼痛、肿胀、偶尔腿部皮肤溃疡等血栓后综合征见于1／3发生过DVT的患者。血栓后综合征可出现较早,也可迟至10年才出现,总的发病率为2年23%,5年28%。患者如使用弹力加压袜至少2年以上,腿部病变的发生率可     

Seroprevalence of herpes simplex virus type 2 and characteristics associated with undiagnosed infection: New York City, 2004

BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection is associated with substantial morbidity and increased risk for human immunodeficiency virus acquisition. We describe HSV-2 seroprevalence in adult New Yorkers, and examine the relationship between select characteristics, infection, and diagnosis. METHODS: HSV-2 seroprevalence and risk factors were measured using the 2004 New York City Health and Nutrition Examination Survey, a population-based cross-sectional survey of adults. HSV-2 seroprevalence and corresponding 95% confidence intervals were computed for select characteristics. Associations between proposed risk factors and HSV-2 infection and diagnosis were estimated using unadjusted and adjusted odds ratios. RESULTS: Nearly 28% of adults were infected with HSV-2; 88.4% of HSV-2 positive persons were undiagnosed. Black women had the highest seroprevalence (59.7%) of any sex or race/ethnicity group. Women, non-Hispanic blacks, and Hispanics (vs. non-Hispanic whites), and men who have sex with men were at greater odds of HSV-2 infection. Among HSV-2 infected individuals, non-Hispanic blacks (vs. non-Hispanic whites), uncircumcised men, and those with no routine place of care were less likely to be diagnosed. CONCLUSIONS: HSV-2 is highly prevalent and largely undiagnosed in New York City; seroprevalence varies by subgroup. Targeted HSV-2 screening, counseling and treatment may help reduce transmission of HSV-2 and human immunodeficiency virus.     

Congenital plaque-type glomuvenous malformations associated with fetal pleural effusion and ascites

Glomuvenous malformations are hereditary vascular anomalies, usually without extracutaneous involvement. We report two cases of extensive thoracic plaque-type glomuvenous malformation in newborns who had previously been diagnosed in utero with pleural effusion and ascites, suggesting a pathogenic link between the two conditions.     

Purchasing behavior and calorie information at fast-food chains in New York City, 2007

We surveyed 7318 customers from 275 randomly selected restaurants of 11 fast food chains. Participants purchased a mean of 827 calories, with 34% purchasing 1000 calories or more. Unlike other chains, Subway posted calorie information at point of purchase and its patrons more often reported seeing calorie information than patrons of other chains (32% vs 4%; P<.001); Subway patrons who saw calorie information purchased 52 fewer calories than did other Subway patrons (P<.01). Fast-food chains should display calorie information prominently at point of purchase, where it can be seen and used to inform purchases.     

Public health in New York City, 2002-2007: confronting epidemics of the modern era

Long after the leading causes of death in the United States shifted from infectious diseases to chronic diseases, many public health agencies have not established effective policies and programmes to prevent current health problems. Starting in 2002, the New York City health department, an agency with a long history of innovation, undertook initiatives to address chronic disease prevention and control, as well as to modernize methods to address persistent health problems. All the initiatives relied on an expansive use of epidemiology; actions to prevent disease were based on policy change to create health-promoting environments as well as engagement with the health care system to improve its focus on prevention. Examples of policy-based initiatives are: a multi-component tobacco control programme that included a tax increase, a comprehensive smoke-free air law, hard-hitting anti-tobacco advertising and cessation services; elimination of trans fats from restaurants and a mandate that restaurants post-calorie information on menu boards. Examples of health care initiatives are public health 'detailing' to primary care providers, creation of a city-wide diabetes registry and development of a public health-oriented electronic health record. The infrastructure needed by local health departments to prevent chronic diseases and other modern health problems includes strong information technology systems, skillful epidemiology, expertise in communications using modern media, policy-making authority and, most importantly, political support.     

Kindler syndrome in native Americans from Panama: report of 26 cases

OBJECTIVE: To investigate the clinical, genetic, and laboratory features of 26 patients with Kindler syndrome. DESIGN: Case series of patients recruited when they were seen at outpatient consultations in the Department of Dermatology at the Changuinola Hospital in Bocas del Toro, Panama, between May 1986 and December 1990. SETTING: Clinical history, physical examination, and laboratory studies were done at a community hospital in Panama. Twelve of the patients had further studies performed at a children's hospital in Costa Rica. PATIENTS: A total of 26 patients were entered into the study. They were members of the Ng?be-Buglé tribe and resided in isolated villages in rural Panama. RESULTS: The major findings were skin fragility with blistering (100%), poikiloderma (96%), photosensitivity (92%), severe cutaneous atrophy (89%), hyperkeratosis of the palms and soles (81%), congenital acral blisters (81%), severe periodontal disease (81%), and phimosis (80% of male subjects). In 1 large family with 10 patients, inheritance of Kindler syndrome followed that of an autosomal recessive disease. Karyotypes in 3 patients and 1 unaffected father were normal. Findings from ultrastructural studies showed replication of lamina densa in 10 patients. CONCLUSIONS: To our knowledge, this study represents the largest series to date of patients with Kindler syndrome. The clinical features confirm previously reported cases, and segregation analysis confirms its autosomal recessive inheritance. We also report severe phimosis as a complication, which has not been previously described in this syndrome.     

Neonatal-onset multisystem inflammatory disorder: the emerging role of pyrin genes in autoinflammatory diseases

Neonatal-onset multisystem inflammatory disorder (NOMID) is a rare congenital disorder characterized by a neonatal-onset urticarial rash, arthropathy, recurrent fevers, and central nervous system disease. We report 3 cases in which patients presented with neonatal-onset urticarial eruption and other organ involvement of varying severity. Genetic testing of 2 of these patients revealed previously unreported genetic mutations in exon 3 of the CIAS1 gene, a recently discovered member of the pyrin gene family. The third patient did not demonstrate a CIAS1 mutation. These cases illustrate the genetic basis of NOMID, an autoinflammatory disorder, and highlight the emerging role of the pyrin gene family in the regulation of nuclear factor kappaB signaling and other pathways involved in inflammation and apoptosis.     

Kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon

Kasabach-Merritt phenomenon is a serious coagulopathy associated with kaposiform hemangioendothelioma (KHE), tufted angioma, and possibly other vascular neoplasms. KHE presenting in the absence of Kasabach-Merritt phenomenon is rare, although tufted angioma frequently occurs without thrombocytopenia. We retrospectively reviewed 10 cases of KHE without Kasabach-Merritt phenomenon. The tumors appeared as soft tissue masses with the overlying skin being either normal, erythematous, or violaceous. There were no radiologic or microscopic differences in noncoagulopathic KHE as compared with coagulopathic KHE. Evidence of platelet trapping and hemosiderin deposition was seen histologically, despite normal serum platelet levels. All KHE were less than 8 cm in diameter, suggesting that tumors that grow no larger than this size are less likely to trap platelets in sufficient quantity to cause thrombocytopenia. Our series confirms that KHE appears with a wide spectrum of behavior and response to treatment. The decision as to whether or not to treat a noncoagulopathic KHE should be based on the size and location of the tumor and the possible side effects of therapy.