The Lynch syndrome is hereditary nonpolyposis in patients with colorectal cancer. This diagnosis has implications for treatment and for the risk of cancer among family members. In this study of 1066 ...patients with newly diagnosed colorectal cancer, 23 patients and 52 family members were positive for Lynch syndrome mutations. Had the criteria of age and the presence or absence of a family history been used to select patients for genetic screening, many mutations would have remained undetected.
In 1066 patients with newly diagnosed colorectal cancer, 23 patients (and 52 family members) were positive for Lynch syndrome mutations. Routine screening for hereditary nonpolyposis may be beneficial to patients and their family members.
Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is becoming increasingly possible owing to technical advances. Even when screening is technically feasible, however, it does not necessarily follow that it is desirable.
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Issues that affect screening include the accuracy, sensitivity, and specificity of the test, the benefit to the patient, the possibly negative ramifications of the results, and the cost.
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One disease discussed as a plausible candidate for screening is the Lynch syndrome (hereditary nonpolyposis colorectal cancer).
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The Lynch syndrome is caused mainly by mutations in the DNA mismatch-repair genes
MLH1, MSH2, MSH6,
and . . .
Dendritic cell (DC)-based therapy has proven to be effective in patients with malignant lymphoma, melanoma, and renal and prostate carcinoma. In this phase I clinical trial, we have shown that ...patients with advanced gynaecological malignancies can be effectively vaccinated with DC pulsed with keyhole limpet haemocyanin (KLH) and autologous tumour antigens. Two patients with uterine sarcoma and six subjects with ovarian carcinoma received three to 23 intracutaneous injections of antigen-pulsed DC at 10-day or 4-week intervals. Three patients showed stable disease lasting 25 to 45 weeks, and five experienced tumour progression within the first 14 weeks. KLH- and tumour lysate-specific delayed-type hypersensitivity (DTH) reactions were observed in six and one patient, respectively. Lymphoproliferative responses to KLH and to tumour lysate stimulation were recorded in six patients and in two patients respectively. Tumour antigen-stimulated interferon-gamma (IFN-gamma) secretion by peripheral blood mononuclear cells (PBMC) in one patient was consistent with a T(H) type 1 cytokine bias. The treatment was safe, well tolerated, immunologically active and except for local cutaneous hypersensitivity devoid of significant adverse effects.
Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the ...potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC.
Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients.
Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia.
This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.
A two-photon-activatable photoacid generator, based on a bis(diarylamino) styrylbenzene core with covalently attached sulfonium moieties, has been synthesized. The photoacid generator has both a ...large two-photon absorption cross section ( δ = 690 × 10-50centimeter4second per photon) and a high quantum yield for the photochemical generation of acid (φH
+= 0.5). Under near-infrared laser irradiation, the molecule produces acid after two-photon excitation and initiates the polymerization of epoxides at an incident intensity that is one to two orders of magnitude lower than that needed for conventional ultraviolet-sensitive initiators. This photoacid generator was used in conjunction with a positive-tone chemically amplified resist for the fabrication of a three-dimensional (3D) microchannel structure.
Acute lung injury (ALI) is well defined in humans, but there is no agreement as to the main features of acute lung injury in animal models. A Committee was organized to determine the main features ...that characterize ALI in animal models and to identify the most relevant methods to assess these features. We used a Delphi approach in which a series of questionnaires were distributed to a panel of experts in experimental lung injury. The Committee concluded that the main features of experimental ALI include histological evidence of tissue injury, alteration of the alveolar capillary barrier, presence of an inflammatory response, and evidence of physiological dysfunction; they recommended that, to determine if ALI has occurred, at least three of these four main features of ALI should be present. The Committee also identified key "very relevant" and "somewhat relevant" measurements for each of the main features of ALI and recommended the use of least one "very relevant" measurement and preferably one or two additional separate measurements to determine if a main feature of ALI is present. Finally, the Committee emphasized that not all of the measurements listed can or should be performed in every study, and that measurements not included in the list are by no means "irrelevant." Our list of features and measurements of ALI is intended as a guide for investigators, and ultimately investigators should choose the particular measurements that best suit the experimental questions being addressed as well as take into consideration any unique aspects of the experimental design.
Transfusion-related acute lung injury is a leading cause of death associated with the use of blood products. Transfusion-related acute lung injury is a diagnosis of exclusion which can be difficult ...to identify during surgery amid the various physiologic and pathophysiologic changes associated with the perioperative period. As anesthesiologists supervise delivery of a large portion of inpatient prescribed blood products, and since the incidence of transfusion-related acute lung injury in the perioperative patient is higher than in nonsurgical patients, anesthesiologists need to consider transfusion-related acute lung injury in the perioperative setting, identify at-risk patients, recognize early signs of transfusion-related acute lung injury, and have established strategies for its prevention and treatment.
Advancements in methods, technology, and our understanding of the pathobiology of lung injury have created the need to update the definition of experimental acute lung injury (ALI). We queried 50 ...participants with expertise in ALI and acute respiratory distress syndrome using a Delphi method composed of a series of electronic surveys and a virtual workshop. We propose that ALI presents as a "multidimensional entity" characterized by four "domains" that reflect the key pathophysiologic features and underlying biology of human acute respiratory distress syndrome. These domains are
) histological evidence of tissue injury,
) alteration of the alveolar-capillary barrier,
) presence of an inflammatory response, and
) physiologic dysfunction. For each domain, we present "relevant measurements," defined as those proposed by at least 30% of respondents. We propose that experimental ALI encompasses a continuum of models ranging from those focusing on gaining specific mechanistic insights to those primarily concerned with preclinical testing of novel therapeutics or interventions. We suggest that mechanistic studies may justifiably focus on a single domain of lung injury, but models must document alterations of at least three of the four domains to qualify as "experimental ALI." Finally, we propose that a time criterion defining "acute" in ALI remains relevant, but the actual time may vary based on the specific model and the aspect of injury being modeled. The continuum concept of ALI increases the flexibility and applicability of the definition to multiple models while increasing the likelihood of translating preclinical findings to critically ill patients.
Key points
The hypothalamic‐pituitary‐adrenal (HPA) axis habituates to repeated stress exposure.
We studied hypothalamic corticotropin‐releasing hormone (CRH) neurons that form the apex of the HPA ...axis in a mouse model of stress habituation using repeated restraint.
The intrinsic excitability of CRH neurons decreased after repeated stress in a time course that coincided with the development of HPA axis habituation.
This intrinsic excitability plasticity co‐developed with an expansion of surface membrane area, which increased a passive electric load and dampened membrane depolarization in response to the influx of positive charge.
We report a novel structure–function relationship for intrinsic excitability plasticity as a neural correlate for HPA axis habituation.
Encountering a stressor immediately activates the hypothalamic‐pituitary‐adrenal (HPA) axis, but this stereotypic stress response also undergoes experience‐dependent adaptation. Despite the biological and clinical importance, how the brain adjusts stress responsiveness in the long term remains poorly understood. We studied hypothalamic corticotropin‐releasing hormone neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint. Using patch‐clamp electrophysiology in acute slices, we found that the intrinsic excitability of these neurons substantially decreased after daily repeated stress in a time course that coincided with their loss of stress responsiveness in vivo. This intrinsic excitability plasticity co‐developed with an expansion of surface membrane area, which increased a passive electric load, and dampened membrane depolarization in response to the influx of positive charge. Multiphoton imaging and electron microscopy revealed that repeated stress augmented ruffling of the plasma membrane, suggesting an ultrastructural plasticity that may efficiently accommodate the membrane area expansion. Overall, we report a novel structure–function relationship for intrinsic excitability plasticity as a neural correlate for adaptation of the neuroendocrine stress response.
Key points
The hypothalamic‐pituitary‐adrenal (HPA) axis habituates to repeated stress exposure.
We studied hypothalamic corticotropin‐releasing hormone (CRH) neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint.
The intrinsic excitability of CRH neurons decreased after repeated stress in a time course that coincided with the development of HPA axis habituation.
This intrinsic excitability plasticity co‐developed with an expansion of surface membrane area, which increased a passive electric load and dampened membrane depolarization in response to the influx of positive charge.
We report a novel structure–function relationship for intrinsic excitability plasticity as a neural correlate for HPA axis habituation.
Mesenchymal stem/stromal cells (MSCs) have demonstrated efficacy in pre-clinical models of inflammation and tissue injury, including in models of lung injury and infection. Rolling, adhesion and ...transmigration of MSCs appears to play a role during MSC kinetics in the systemic vasculature. However, a large proportion of MSCs become entrapped within the lungs after intravenous administration, while the initial kinetics and the site of arrest of MSCs in the pulmonary vasculature are unknown. We examined the kinetics of intravascularly administered MSCs in the pulmonary vasculature using a microfluidic system in vitro and intra-vital microscopy of intact mouse lung. In vitro, MSCs bound to endothelium under static conditions but not under laminar flow. VCAM-1 antibodies did not affect MSC binding. Intravital microscopy demonstrated MSC arrest at pulmonary micro-vessel bifurcations due to size obstruction. Retention of MSCs in the pulmonary microvasculature was increased in Escherichia coli-infected animals. Trapped MSCs deformed over time and appeared to release microvesicles. Labelled MSCs retained therapeutic efficacy against pneumonia. Our results suggest that MSCs are physically obstructed in pulmonary vasculature and do not display properties of rolling/adhesion, while retention of MSCs in the infected lung may require receptor interaction.
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