The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox ...catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.
Background: Immune-compromised individuals are at increased risk for developing aggressive Epstein-Barr virus (EBV)–associated lymphoproliferative disorders after primary EBV infection or for ...reactivation of a preexisting latent EBV infection. We evaluated the effect of depsipeptide, a histone deacetylase inhibitor, on EBV-positive lymphoblastoid cell lines (LCLs) and Burkitt lymphoma cell lines in a mouse model and explored its mechanism of action in vitro. Methods: We studied EBV-transformed LCLs, which express a latent III (Lat-III) viral gene profile, as do some EBV-positive lymphoproliferative malignancies, and Burkitt lymphoma cell lines, which express a Lat-I viral gene profile. Cell lines were used to characterize depsipeptide-induced apoptosis, which was evaluated by flow cytometry. Flow cytometry, western blot analyses, and histone deacetylase inhibitors were used to investigate components of prodeath and survival pathways in vitro. We studied depsipeptide’s effects on survival with a mouse xenograft model of EBV-positive human B-cell tumors (groups of 10 mice). All statistical tests were two-sided. Results: Depsipeptide (5 mg/m2 of body surface area) treatment was associated with statistically significantly improved survival of mice carrying Lat-III EBV–positive LCL tumors, compared with that of control-treated mice (day 30: for depsipeptide-treated mice, 90% survival, 95% confidence interval CI = 73.2% to 100%; for control-treated mice, 20% survival, 95% CI = 5.79% to 69.1%; P<.001), but it was not associated with survival of mice carrying Lat-I EBV–positive Burkitt lymphoma tumors. Depsipeptide induced apoptosis in 64% of LCLs and in 14% of EBV-positive Burkitt lymphoma cells in vitro. Depsipeptide-treated LCL cultures had two distinct cell populations—one sensitive and one resistant to depsipeptide. Depsipeptide-mediated apoptosis was associated with a 12-fold increased level of active caspase 3, but some apoptosis persisted despite z-VAD-fmk treatment to inhibit caspase activity. Depsipeptide-resistant LCLs expressed higher levels of latent membrane protein 1 (LMP1; P = .017), BCL2 (P = .032), and nuclear factor κB (NF-κB) (P<.001) than depsipeptide-sensitive LCLs; this resistance was circumvented by treatment with PS-1145, an inhibitor of NF-κB activation (P<.001). Conclusions: Apoptosis is induced by depsipeptide via caspase-dependent and -independent pathways in Lat-III EBV–positive LCLs and is enhanced by inhibiting NF-κB activity. Depsipeptide as a treatment for Lat-III EBV–associated lymphoproliferative disorders should be explored further in clinical trials.
This study compared safety, tolerability, and immunogenicity of the Oka/Merck varicella vaccine and VARILRIX™ Oka-RIT strain SmithKline Beecham Biologicals in healthy children 12–24 months of age. ...Subjects were randomized in this double blind study to receive either a single dose of Oka/Merck varicella vaccine, (∼50,000 plaque forming units (PFU), Group A or ∼16,000
PFU, Group B) or 1 dose of VARILRIX™, (∼40,000
PFU/dose, Group C). Safety profiles in each treatment group were similar. The proportions of subjects achieving a 6-week postvaccination titer⩾5
gpELISA units in Groups A, B or C were 97.1, 95.2 and 85.6%, respectively.
Achieving transplantation tolerance remains an unresolved clinical challenge. Although bone marrow transplantation (BMT) induces mixed chimerism that establishes transplantation tolerance, the ...preconditioning regimens required for BMT to succeed are too prohibitive for routine use. Recently, embryonic stem (ES) cells have emerged as a potential alternative cell source to bone marrow cells. However, it remains difficult to efficiently differentiate these cells into hematopoietic cells. Here, we tested whether bone morphogenetic protein-4 (BMP-4)-treated or HOXB4-transduced ES-derived hematopoietic cells engraft permanently inducing long-term mixed chimerism.
Initially, 129 SvJ R1 ES cells (H-2) were treated with BMP-4 for 36 hr. The cells were phenotyped and polymerase chain reaction studies were performed. The robustness of mixed chimerism was tested using mixed lymphocyte cultures and skin grafts. Chimeric MRL (H-2) animals received grafts from 129SvJ (H-2), Balb/c (H-2) or class II (H-2) donor mice, and graft survival was monitored. Additionally, HOXB4-transduced ES cells were shown to more efficiently differentiate into hematopoietic progenitor cells that engrafted in allogenic and syngeneic recipient mice.
BMP-4 treatment induced Sca-1 expression and up-regulated HOXB4, BMP-4, and BMP receptor gene expressions. The cells induced transient mixed chimerism, whereas cells derived from HOXB4-transduced ES cells engrafted long term (>100 days).
Although BMP-4 promotes hematopoiesis of ES cells, its impact is only transient, whereas permanent ectopic expression of HOXB4 significantly confers self-renewal and long-term engraftment of ES-derived hematopoietic cells. This strategy could facilitate the establishment of an alternative source of hematopoietic cells that could induce transplantation tolerance.
OBJECTIVES: To assess the prevalence of tuberculous infection and active tuberculosis (TB) in old age homes in Hong Kong and to determine whether there is institutional transmission in these homes.
...DESIGN: Cross‐sectional.
SETTING: Old age homes.
PARTICIPANTS: Total of 2,243 residents, representing 84.6% of all residents in 15 old age homes; 1,698 were women, and 545 were men, with an average age of 82.
MEASUREMENTS: All residents had a questionnaire‐based interview, medical record review, two‐stage tuberculin testing using two units purified protein derivative‐RT23, and a chest x‐ray. Those with radiological abnormalities had sputum examined for acid‐fast bacilli.
RESULTS: The estimated prevalence rate of active TB in this population was 669 per 100,000, significantly higher in men than in women (1,101 per 100,000 vs 530 per 100,000). The proportion with positive tuberculin reactivity (≥10 mm induration) after two‐stage testing was 68.6%, significantly higher in men than in women. There was no evidence of active transmission of disease in these old age homes, with restriction fragment length polymorphism (RFLP) analysis performed on five cases of active pulmonary TB in the home with the highest rate of TB showing unique RFLP patterns.
CONCLUSION: The rate of active TB and TB infection in old age homes in Hong Kong is still high. Because treatment for latent TB carries a high risk for liver dysfunction in this population, clinicians and other healthcare workers need a high index of suspicion and to diagnose and treat this disease as early as possible to prevent transmission.
Four cases of nasopharyngeal granulomatous inflammation after radiotherapy for undifferentiated carcinoma were analyzed for tuberculosis, and the histologic features were compared.
We conducted a ...retrospective study with analysis of tuberculosis by Ziehl Neelsen staining and polymerase chain reaction analysis for Mycobacterium tuberculosis DNA on histologic materials.
Three patients had previous nasopharyngeal undifferentiated carcinoma, one had previous metastatic undifferentiated carcinoma to cervical lymph nodes, and all patients received similar radiotherapy regimen. The light microscopic features were similar with epithelioid histiocytes and granulomas with Langhan's giant cells. In 3 cases, acid-fast bacilli were identified by Ziehl Neelsen stain, and 1 was negative. The results of 2 cases were confirmed by polymerase chain reaction analysis for Myocbacterium tuberculosis DNA.
Granulomatous reaction after radiotherapy of nasopharyngeal undifferentiated carcinoma can be caused by tuberculosis.
Diligent search for organisms in postirradiation granulomatous inflammation is warranted to avoid missing an occult tuberculosis infection.
We retrospectively studied 19 cases of nasal NK/T-cell lymphoma for various potential prognostic factors and performed real-time quantitative polymerase chain reaction for Epstein-Barr virus (EBV) ...viral load in tumor tissue. Patients with a low EBV viral load (<1 copy per cell) more frequently survived for more than 2 years compared with patients with a high EBV viral load (>/=1 copies/cell) (7/7 vs 3/9; P = .014; Fisher exact test). Furthermore, the patients with low EBV viral loads had a better overall survival than patients with high viral loads (50% accumulative survival: not reached vs 4-5 months; Kaplan-Meier survival analysis; P = .049). In contrast, the overall survival of the patients did not correlate with the extent of lesion, age, stage, necrosis, histologic subtypes, CD56 expression, or angiocentric or angiodestructive growth pattern. Our findings suggest that the EBV viral load in tumor tissues is a useful indicator for predicting outcome of nasal NK/T-cell lymphoma.
Bilateral breast carcinomas may represent contralateral metastases or new primary tumors. The presence of carcinoma in situ, a lower grade, or a different histotype in the second tumor is considered ...a clinical criterion for a second primary tumor. In this study, 26 bilateral breast carcinomas from 13 patients were analyzed based on clinical criteria, and the results were compared with those obtained by partial allelotyping using 47 markers at 7 chromosomal arms. Of the 8 synchronous tumors, 5 were concluded to be distinct primary tumors using clinical criteria; some were confirmed by partial allelotyping. In the remaining 3 cases, partial allelotyping showed distinct primary tumors. Five patients had metachronous carcinomas with 3 distinct primary tumors, 1 metastasis, and 1 that was uncertain by clinical criteria. Three cases were confirmed by partial allelotyping, and the uncertain case was shown to be distinct primary tumors. No discrepant results were noted. Stringent application of clinical criteria is accurate for differentiating second primary tumors from metastases.
Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with ...acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis.
We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated.
A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point).
Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).
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