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Biomedical subjects

Michael Wang

Publications and source records attributed to Michael Wang.

At least 19 recordsLinked to original sources
PubMed2025

CSF proteogenomics implicates novel proteins and humoral immunity in Alzheimer's disease risk.

We profiled 2,961 cerebrospinal fluid (CSF) proteins in 1,005 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 1,066 proteins not measured in prior studies, using mass spectrometry (MS). We mapped protein quantitative trait loci (pQTLs) in CSF, compared them with brain and plasma pQTLs, and integrated them with Alzheimer's disease (AD) genome-wide association study (GWAS) data. We identified 1,417 index cis pQTLs for 654 unique genes and 130 index trans pQTLs for 94 unique genes. Cross-tissue and cross-proteomic-platform comparisons show broad consistency between MS-based CSF pQTLs and MS-based brain pQTLs as well as affinity-based CSF and plasma pQTLs. Lastly, through integrating CSF pQTLs with the largest AD GWAS, we identified 24 candidate AD causal proteins in CSF, including 10 novel and 14 previously identified in either brain, CSF, or plasma using similar approaches. These CSF AD candidate causal proteins are involved in immune response - notably humoral immunity (3 of 24) - that expands the role of the immune system in AD beyond innate immunity, as well as lysosomal function and neurovascular growth and remodeling. Together, our findings provide novel insights into AD biology and new targets for biomarker and therapeutic development.

Journal Article↗
PubMed2006

Dose-related safety and immunogenicity of baculovirus-expressed trivalent influenza vaccine: a double-blind, controlled trial in adult patients with non-Hodgkin B cell lymphoma.

In 27 patients randomized to receive commercial trivalent influenza vaccine (TIV) containing 15 microg of the hemagglutinin (HA) of influenza A (H3N2 and H1N1) and B virus or a recombinant vaccine (rHAO) containing 15, 45, or 135 microg of each HA, reactogenicity was minor. Among patients with similar prevaccination titers, 40% given 45 microg and 60% given 135 microg of rHAO developed an increase in influenza A/H3 neutralizing antibody levels; there were no increases in 4 given TIV. For each vaccine, the highest frequencies of increases in neutralizing antibody levels and the highest mean titers occurred in those given the 135- microg vaccine.

Antibodies, Viral↗
PubMed2006

Safety and efficacy of once-per-cycle pegfilgrastim in support of ABVD chemotherapy in patients with Hodgkin lymphoma.

The objective of this prospective study was to examine the safety and efficacy of pegfilgrastim in support of chemotherapy regimens that are administered every 14 d. Patients with Hodgkin lymphoma receiving standard ABVD (doxorubicin, bleomycin, vinblastine, and decarbazine) chemotherapy every 14 d were eligible for the study. All patients received one fixed dose of 6 mg pegfilgrastim approximately 24h after each ABVD infusion. Absolute neutrophil counts (ANCs) were measured weekly while on therapy. After completion of therapy, ANCs were measured every 3-4 months for 2 years, and every 6 months thereafter. Twenty-three patients received 115 courses (230 doses) of ABVD. Nadir ANC below 0.5 x 10(9)/L was observed only in two cases (1.1%), and ANC counts on the day of ABVD therapy below 1 x 10(9)/L was observed only once (0.4%). No neutropenic fever was observed. Two hundred and fifteen (93.5%) doses of ABVD were given on time as scheduled. Grade 3/4 bone pain was observed after 0.4% of ABVD doses, and bleomycin lung toxicity was observed in two patients. With a median follow-up of 29 months after completion of ABVD, no myelodysplastic syndrome was observed. Two patients relapsed and subsequently underwent successful stem cell collection and transplantation. Pegfilgrastim was found to be safe in support of ABVD chemotherapy that is administered every 14 d. Pegfilgrastim was also effective in maintaining ABVD dose intensity, and keeping planned dose of chemotherapy on schedule.

Adult↗
PubMed2006

Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies.

We discovered that monoclonal antibodies (mAbs) specific to human beta(2)-microglobulin (beta(2)M) induce apoptosis in vitro and were therapeutic in mouse models of myeloma and other hematological tumor cells. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms. The mAbs induced cell death via recruiting MHC class I molecules to lipid rafts and activating Lyn and PLCgamma2, leading to activated JNK and inhibited PI3K/Akt and ERK, compromised mitochondrial integrity, and caspase-9-dependent cascade activation. Although the expression of beta(2)M on normal hematopoietic cells is a potential safety concern, the mAbs were selective to tumor-transformed cells and did not induce apoptosis of normal cells. Therefore, such mAbs offer the potential for a therapeutic approach to hematological malignancies.

Animals↗
PubMed2006

Use of bortezomib in B-cell non-Hodgkin's lymphoma.

The ubiquitin-proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Bortezomib (Velcade, formerly known as PS-341) is a potent proteasome inhibitor. In preclinical studies, bortezomib has demonstrated activity against a variety of B-cell malignancies by inducing apoptosis and sensitizing tumor cells to radiation or chemotherapy. Based on these findings, clinical trials have been conducted with bortezomib in B-cell non-Hodgkin's lymphoma. In these studies, bortezomib was generally well tolerated with manageable toxicities and showed promising clinical activity. Mantle cell lymphoma was significantly more sensitive to bortezomib than other non-Hodgkin's lymphomas. Bortezomib may have far-reaching potential in the treatment of B-cell non-Hodgkin's lymphoma.

Antineoplastic Agents↗
PubMed2005

High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine.

PURPOSE: To determine the response, failure-free survival (FFS), and overall survival rates and toxicity of rituximab plus an intense chemotherapy regimen in patients with previously untreated aggressive mantle-cell lymphoma (MCL). PATIENTS AND METHODS: This was a prospective phase II trial of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD; considered one cycle) alternating every 21 days with rituximab plus high-dose methotrexate-cytarabine (considered one cycle) for a total of six to eight cycles. RESULTS: Of 97 assessable patients, 97% responded, and 87% achieved a complete response (CR) or unconfirmed CR. With a median follow-up time of 40 months, the 3-year FFS and overall survival rates were 64% and 82%, respectively, without a plateau in the curves. For the subgroup of patients < or = 65 years of age, the 3-year FFS rate was 73%. The principal toxicity was hematologic. Five patients died from acute toxicity. Four patients developed treatment-related myelodysplasia/acute myelogenous leukemia, and three patients died while in remission from MCL. A total of eight treatment-related deaths (8%) occurred. CONCLUSION: Rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine is effective in untreated aggressive MCL. Toxicity is significant but expected. Because of the shorter FFS concurrent with significant toxicity in patients more than 65 years of age, this regimen is not recommended as standard therapy for this age subgroup. Larger prospective randomized studies are needed to define the role of this regimen in the treatment of MCL patients compared with existing and new treatment modalities.

Administration, Oral↗
PubMed2005

Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma.

The value of thalidomide-dexamethasone was assessed in 26 consecutive, previously untreated patients with multiple myeloma of high tumor mass. All showed Hgb < 8.5 g/dL, serum calcium > 11.5 mg/dL, or both. The response rate was 73%, frequency of early death < 3 months was 5%, projected median survival was 30 months, and projected median remission time was 25 months. There were no occurrences of grade 3 or 4 neutropenia or thrombocytopenia, so that serious infection occurred in only 12% of patients. Thalidomide-dexamethasone was useful for these patients with advanced disease because of the high response rate and acceptable survival, with a low frequency of serious complications.

Adult↗
PubMed2005

Awareness in dementia: conceptual issues.

There has been a recent proliferation of studies exploring awareness in people with dementia and, as is the case with similar studies in other clinical areas, results are generally mixed and inconsistent. One of the reasons underlying variability in study results relates to the complexities around the concept of awareness itself. Two sources of conceptual problems are explored. First, the meaning of awareness is examined and, within the dementia literature, various conceptualizations of awareness are identified which could be traced to three broad frameworks within which awareness and related terms are conceived. Differences between meanings of awareness are thus highlighted and the importance of making such differences explicit in studies was discussed. Second, the relational aspect of awareness is raised as a crucial issue determining the phenomenon of awareness elicited in clinical practice. Thus, in dementia, awareness is related to various "objects" including the illness as a whole, memory problems, activities of daily living, affective changes and many others. In each case, however, the object of awareness will elicit a different phenomenon of awareness, again carrying implications for the generalizability of study results. Clarification of conceptual problems is essential for future work in this area in order that empirical studies can provide meaningful answers concerning the therapeutic and predictive validity of different aspects of awareness.

Activities of Daily Living↗
PubMed2004

Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.

PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrom's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.

Adult↗
PubMed2004

Returning home after intensive care: a comparison of symptoms of anxiety and depression in ICU and elective cardiac surgery patients and their relatives.

OBJECTIVE: This study gathered data on symptoms of anxiety and depression in patients and relatives after discharge from intensive care and examined whether the intensive care population differ from an elective cardiac surgery group with regards to their anxiety and depression symptom reporting. DESIGN AND SETTING: A single measurement point matched group comparison study in an ICU follow-up programme. PATIENTS AND PARTICIPANTS: Twenty ICU patients and their relatives and a matched comparison group of 15 elective cardiac surgery patients and their relatives. MEASUREMENTS AND RESULTS: Patients and relatives completed the Hospital Anxiety and Depression Scale. Relatives answered an open question to explore the perceived impact of Intensive care/cardiac surgery on their lives. ICU patients' relatives reported significantly higher number of symptoms of anxiety than did ICU patients, higher number of symptoms of depression than cardiac surgery patients' relatives, and more troubling and life-altering experiences than the relatives of cardiac surgery patients. CONCLUSIONS: Relatives of ICU patients also suffer anxiety and depression, and services should address this need. Group differences suggest that ICU patients' relatives have "unique" characteristics of depression symptom reporting.

Anxiety↗
PubMed2004

Loss of Bim allows precursor B cell survival but not precursor B cell differentiation in the absence of interleukin 7.

Interleukin (IL)-7 is a stromal cell-derived cytokine required for the survival, proliferation, and differentiation of B cell precursors. Members of the Bcl-2 family of proteins are known to have profound effects on lymphocyte survival, but not lymphocyte differentiation. To distinguish the relative dependence on IL-7 of B cell precursor survival versus B cell differentiation, the combined effects of lack of IL-7 and lack of the proapoptotic Bcl-2 relative, Bim, were studied. Bim is expressed to varying degrees in all B cell precursors and B cells. Lack of Bim compensated for lack of IL-7 in the survival of pro-, pre-, and immature B cells; however, lack of Bim did not substitute for the requirement for IL-7 in B cell precursor differentiation or B cell precursor proliferation. Precursor B cell survival is more dependent on sufficient levels of IL-7 than precursor B cell differentiation because the number of B cells and their precursors were reduced by half in mice heterozygous for IL-7 expression, but were restored to normal numbers in mice also lacking Bim. Hence, Bim and IL-7 work together to control the survival of B cell precursors and the number of B cells that exist in animals.

Animals↗
PubMed2004

Colitis in patients with breast carcinoma treated with taxane-based chemotherapy.

BACKGROUND: Colitis is a rare but serious gastrointestinal complication associated with taxane-based chemotherapy in patients with cancer. The incidence, clinical presentation, and outcome of colitis in patients with breast carcinoma treated with taxane-based chemotherapy is not known. METHODS: The authors searched their electronic database and identified patients with breast carcinoma who were treated with taxane-based chemotherapy between January 1997 and December 1999. Patients diagnosed with colitis were identified and their presentation and clinical outcomes were analyzed. RESULTS: During the study period, 1350 patients received taxane-based chemotherapy. Sixty-four patients were admitted to The University of Texas M. D. Anderson Cancer Center (Houston, TX) (73 admissions) for gastrointestinal complications. Neutropenia and/or fever accounted for 56 of these admissions. Fourteen patients (16 admissions) were diagnosed with colitis. All had abdominal pain at median Day 6 of their chemotherapy cycle (range, 3-8 days), with or without other symptoms. Computed tomography scans of the abdomen and pelvis were abnormal for the 10 patients tested, whereas only 3 of the 9 patients who underwent radiographic abdominal series had abnormal findings. Two patients had a colonoscopy that confirmed the diagnosis of colitis. Blood cultures were positive in only 3 (20%) of 15 colitis events. All eight patients tested for Clostridium difficile toxin were negative. One patient died of sepsis. An autopsy subsequently revealed cecal ulceration. Two patients had bowel perforations requiring hemicolectomy. Colitis recurred in two patients after they resumed taxane-based chemotherapy without dose reduction. Dose reductions prevented the recurrence of colitis in seven patients. Treatment discontinuation of taxane-based chemotherapy also prevented disease recurrence. CONCLUSIONS: Acute abdominal pain in patients with breast carcinoma treated with taxane-based chemotherapy signaled a potentially fatal colitis, and warrants aggressive supportive care. Dose reduction or discontinuation of taxane-based chemotherapy may prevent the recurrence of colitis.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.

PURPOSE: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles. RESULTS: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. CONCLUSION: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.

Adult↗
PubMed2004

Constitutive association of the proapoptotic protein Bim with Bcl-2-related proteins on mitochondria in T cells.

Apoptosis in activated T cells in vivo requires the proapoptotic Bcl-2 family member Bim. We show here that, despite its ability to bind LC8, a component of the microtubule dynein motor complex, most of the Bim in both healthy and apoptotic T cells is associated with mitochondria, not microtubules. In healthy resting T cells Bim is bound to the antiapoptotic proteins Bcl-2 and Bcl-x(L). In activated T cells, levels of Bcl-2 fall, and Bim is associated more with Bcl-x(L) and less with Bcl-2. Our results indicate that, in T cells, Bim function is regulated by interaction with Bcl-2 family members on mitochondria rather than by sequestration to the microtubules.

Animals↗
PubMed2004

Influence of physicochemical properties and intestinal region on the absorption of 3-fluoro-2-pyrimidylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, a water insoluble thrombin inhibitor, in dogs.

In this paper, we describe the physicochemical and biopharmaceutical properties of 3-fluoro-2-pyrimidylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, a direct thrombin inhibitor (1, Fig. 1). Three crystalline forms were characterized and studies were planned to investigate the absorption characteristics of the three selected crystalline forms. Due to the short half-life observed in preclinical species, regional absorption studies were also conducted to support potential controlled release formulation development. Results showed that the absorption of 1 was dependent on the surface area of the particles administered as suspensions and was independent of the crystal forms. From Caco-2 cell transport studies, it was determined that the permeability of 1 was high. Based on the low aqueous solubility it would be classified as a class 2 compound in the Biopharmaceutics Classification System. Regional absorption results suggested that the compound was absorbed along the gastrointestinal tract in Beagle dogs, however colonic absorption appeared to be reduced by slower dissolution.

Acetamides↗
PubMed2004

Developing a rating scale for projected stories.

The Six-part Story Method (6PSM) is a projective tool in wide use by dramatherapists in the UK, USA and Israel (Lahad & Ayalon, 1993). In contrast to projective tests used by psychotherapists and psychologists, the 6PSM has never been the subject of any validation or reliability studies. This study reports on the identification of scale items to describe the manifest content of six-part stories. In all, 26 statements with acceptable inter-rater reliability have been identified. These statements were used to rate stories produced by clinicians (N = 24) mainstream community mental health patients (N = 21) and patients with a borderline personality disorder (N = 19). Some features that were expected to be indicators of an author with a BPD diagnosis proved to be as common in stories from other authors. However, a scale of eight items was identified that differentiated well between authors with a BPD diagnosis and others, with adequate test-retest and inter-rater reliability. Concurrent validity was tested against the Structured Clinical Interview for DSM-IV Axis II (SCID-II), the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM) and the Inventory of Interpersonal Problems--Short Form (IIP-32).

Humans↗