Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8 T cells to suppress anti-tumor immunity.

Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8 T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA.

TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate.

Chronic T-cell receptor (TCR) signaling in the tumor microenvironment is known to promote T-cell dysfunction. However, we reasoned that poorly immunogenic tumors may also compromise T cells by impairing their metabolism. To address this, we assessed temporal changes in T-cell metabolism, fate, and function in models of B-cell lymphoma driven by Myc, a promoter of energetics and repressor of immunogenicity.

Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes.

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN.

High vacuum equipment for the measurement of the macroscopic dipole moment of polar molecular crystals.

Polar crystals placed into a charged plate capacitor may experience a mechanical torque. Mounting crystals on a spiral spring allows us to measure the momentum and thus the macroscopic dipole moment of a crystal object. To exclude the influence of ambient conditions (air, ions, electrons), experiments are performed in a high vacuum.

Cross-sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation.

Background: Cutaneous viral infections and immune suppression are risk factors for some forms of nonmelanoma skin cancer; however, their interrelationship is poorly understood.

Objectives: To examine cross-sectional associations between cutaneous viral infections and circulating forkhead-box P3 (FOXP3)-expressing T-regulatory (Treg) cells, suppressive cells that dampen effective antitumour immunity.

Materials And Methods: Blood, eyebrow hair (EBH) and skin swab (SSW) samples were collected from 352 patients 60 years and older undergoing skin screening, without prevalent skin cancer, while participating in an ongoing prospective cohort study of cutaneous viral infections and skin cancer.

T Regulatory Cell Subpopulations Associated with Recent Ultraviolet Radiation Exposure in a Skin Cancer Screening Cohort.

UV radiation (UVR) causing DNA damage is a well-documented risk factor for nonmelanoma skin cancer. Although poorly understood, UVR may also indirectly contribute to carcinogenesis by promoting immune evasion. To our knowledge, we report the first epidemiological study designed to investigate the association between quantitative measures of UVR, obtained using a spectrophotometer, and circulating T regulatory (Treg) cells.

Stochastic polarity formation in molecular crystals, composite materials and natural tissues.

This topical review summarizes the theoretical and experimental findings obtained over the last 20 years on the subject of growth-induced polarity formation driven by a Markov chain process. When entering the growing surface of a molecular crystal, an inorganic-organic composite or a natural tissue, the building blocks may undergo 180° orientational disorder. Driven by configurational entropy, faulted orientations can promote the conversion of a growing non-polar seed into an object showing polar domains.

Long-term efficacy and safety of a nitinol closure clip system for anal fistula treatment.

Introduction: Treatment failure of anal fistula results in high re-occurrence rate.

Material And Methods: Efficacy and safety of a nitinol closure clip system (bear-claw clip) were evaluated for anal fistulae treatment in a 36-month long-term follow-up study.

Results: Twenty-two patients were included.

Challenging dedifferentiated liposarcoma identified by MDM2-amplification, a report of two cases.

Background: Liposarcoma is the most frequent soft tissue sarcoma. Well differentiated liposarcoma may progress into dedifferentiated liposarcoma with pleomorphic histology. A minority additionally features myogenic, osteo- or chondrosarcomatous heterologous differentiation.

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part three: individual patient, complication algorithm and quality manage.

General Design: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). A randomised, placebo controlled, double-blinded, single-centre study is performed at an University Hospital (n = 40 patients for each group). This part presents the course of the individual patient and a complication algorithm for the management of anastomotic leakage and quality management.

[Therapy planning and surgical indications for Crohn-associated anal fistulas].

A prospective study conducted from April 1988 to April 1998 in 83 patients with anal fistulas associated Crohn's diseases registers and evaluates data regarding the type of fistula, the planned therapy, the operative procedure, and the therapy itself. The choice of the operation time with special regard to the type of fistula and the presence of proctitis as well as the interdisciplinary management in cooperation with the gastroenterologist and the strict observance of the operative procedure for the different types of fistulas enable individually defined surgical treatment of anal fistulas associated with Crohn's disease. It is important that the primary intervention be performed by a surgeon who is experienced in classifying the different types of fistulas because of the recurrence rate of 23% and the required interval between the first and final surgical intervention and so that patients are well informed.

[Laparoscopic ileostomy and colostomy in Crohn disease patients].

The indications, operative procedure, postoperative complications and advantages of laparoscopic ileostomy and colostomy as compared with "open" enterostomy are described and demonstrated in our own patients with Crohn's disease. Major indications for laparoscopic enterostomy in patients with Crohn's disease are stenosis, fecal incontinence and complex anal fistulas in those with severe Crohn's proctitis. Most Crohn patients tolerate laparoscopic enterostomy and an increasing number demand this minimally invasive technique.

Deposition of nitrogen-containing compounds to an extensively managed grassland in central Switzerland.

During four intensive observation periods in 1992 and 1993, dry deposition of nitrogen dioxide (NO(2)) and ammonia (NH(3)), and wet deposition of nitrogen (N) were determined. The measurements were carried out in a small, extensively managed litter meadow surrounded by intensively managed agricultural land. Dry deposition of NH(3) was estimated by the gradient method, whereas eddy correlation was used for NO(2).

Mycobacteria of Runyon groups I, II and IV do not play an aetiological role in Crohn's disease.

Objective: In addition to Mycobacterium paratuberculosis, other slow-growing as well as rapid-growing mycobacteria were isolated from mucosa or full thickness samples of intestine from patients with Crohn's disease. The meaning of these data remained unclear. To investigate the possible aetiological role of these rapid- and slow-growing mycobacteria, serosa and mesenteric lymph nodes were also cultivated in the present study.

[Sigmoid diverticulitis in immunosuppressive drug therapy].

In a retrospective study we evaluated the data of 92 patients (41 women, 51 men, age median: 63 years) with diverticulitis of the sigma who were treated surgically in our clinic from January 1986 till December 1992. Twelve patients (13%) suffered from suppression of the immune system due to a corticoid therapy (n = 3), chemotherapy (n = 1), combination of corticoid therapy and chemotherapy (n = 1), combination of chemotherapy and azathioprine, leucopenia due to carbimazole therapy as a side effect (n = 1) and immunosuppression with prednisone, azathioprine and cyclosporine after renal and heart transplantations (n = 5). The therapy was Hartmann's procedure in 5 patients, drainage and loop colostomy in one patient, sigma resection with primary anastomosis without a protective enterostomy in 5 patients and with a loop ileostomy in one patient.

Treatment of anovaginal fistulas with an anocutaneous flap in patients with Crohn's disease.

We report on a new and simple operative technique for closure of anovaginal fistulas with an anocutaneous flap in patients with Crohn's disease. From January 1989 till December 1990 this operation was performed in 10 women with Crohn's disease. Seven of the ten patients suffered from Crohn's proctitis.

Human intestinal diamine oxidase (DAO) activity in Crohn's disease: a new marker for disease assessment?

The key-enzyme for the metabolism of diamines in man is diamine oxidase (DAO). Its highest activities are in the intestinal mucosa, localized in the cytoplasm of the mature enterocytes of the small and large bowel. If the gut is affected by inflammation in Crohn's disease macroscopical changes are observed.

Inhibition of intestinal diamine oxidase by detergents: a problem for drug formulations with water insoluble agents applied by the intravenous route?

One hundred and twenty four water-insoluble drugs were included in a study for their action on diamine oxidase (DAO) after solubilization with 61 detergents. 16 detergents were themselves not water-soluble and were not further investigated. A further 3 detergents affected the extraction procedure and 7 of the remaining 42 detergents themselves inhibited the activity of canine intestinal DAO in vitro.

[Endoscopic resection of colorectal polyps].

In 766 patients, 1413 polyps of the colon and the rectum were resected endoscopically. 79% of the polyps were located in the rectum and sigmoid colon. The histological examination revealed adenomatous polyps in 60%.