Increases in tropical rainfall driven by changes in frequency of organized deep convection.

Increasing global precipitation has been associated with a warming climate resulting from a strengthening of the hydrological cycle. This increase, however, is not spatially uniform. Observations and models have found that changes in rainfall show patterns characterized as 'wet-gets-wetter' and 'warmer-gets-wetter'. These changes in precipitation are largely located in the tropics and hence are probably associated with convection. However, the underlying physical processes for the observed changes are not entirely clear. Here we show from observations that most of the regional increase in tropical precipitation is associated with changes in the frequency of organized deep convection. By assessing the contributions of various convective regimes to precipitation, we find that the spatial patterns of change in the frequency of organized deep convection are strongly correlated with observed change in rainfall, both positive and negative (correlation of 0.69), and can explain most of the patterns of increase in rainfall. In contrast, changes in less organized forms of deep convection or changes in precipitation within organized deep convection contribute less to changes in precipitation. Our results identify organized deep convection as the link between changes in rainfall and in the dynamics of the tropical atmosphere, thus providing a framework for obtaining a better understanding of changes in rainfall. Given the lack of a distinction between the different degrees of organization of convection in climate models, our results highlight an area of priority for future climate model development in order to achieve accurate rainfall projections in a warming climate.

Post-zygotic selection against parental genotypes during larval development maintains all-hybrid populations of the frog Pelophylax esculentus.

BACKGROUND: Hybridization between two species usually leads to inviable or infertile offspring, due to endogenous or exogenous selection pressures. Yet, hybrid taxa are found in several plant and animal genera, and some of these hybrid taxa are ecologically and evolutionarily very successful. One example of such a successful hybrid is the water frog, Pelophylax esculentus which originated from matings between the two species P. ridibundus (genotype RR) and P. lessonae (LL). At the northern border of the distribution all-hybrid populations consisting of diploid (LR) and one or two triploid (LLR, LRR) frog types have been established. Here, the hybrid has achieved reproductive independence from its sexual ancestors and forms a self-sustaining evolutionary unit. Based on the gamete production of these hybrids, certain mating combinations should lead to LL and RR offspring, but these parental forms are absent among the adults. RESULTS: In order to investigate the mechanisms that maintain such an all-hybrid system, we performed a field study and a crossing experiment. In the field we sampled several ponds for water frog larvae at different developmental stages. Genotype compositions were then analysed and life-history differences between the genotypes examined. In the experiment we crossed diploid and triploid males and females from different ponds and determined fertilization success as well as development speed and survival rates of the offspring under high, medium and low food availability. In both parts of the study, we found numerous LL and RR offspring during the egg and early larval stages; but the frequency of these parental genotypes decreased drastically during later stages. In natural ponds almost all of them had disappeared already before metamorphosis; under the more benign experimental conditions the last ones died as juveniles during the following year. CONCLUSIONS: From the combined results we conclude that the absence of parental genotypes in all-hybrid populations is due to post-zygotic selection against them, rather than to pre-zygotic mechanisms that might prevent their formation in the first place. For this post-zygotic selection, genetic mechanisms resulting from low genetic diversity and fixation of deleterious mutations seem to be a more likely explanation than ecological factors.

Beliefs about stress moderate the association between COVID-19-related work demands and burnout symptoms in physicians.

The present study set out to investigate the role of different stress beliefs (positive and negative beliefs about stress, as well as perceived control) on the association between central COVID-19-related work demands and burnout symptoms in physicians during the second lockdown of the SARS-CoV-2 pandemic. N = 154 practicing physicians (mean [SD] age = 37.21 [9.43] years]; 57.14% female) participated in our cross-sectional German-wide online survey and answered questions about sociodemographic factors, their current work situation, their stress beliefs, and their current burnout symptoms. Moderation analyses revealed significant interaction effects between stress beliefs and specific COVID-19-related work demands on the prediction of burnout symptoms, most consistent with respect to perceived control. Positive believes about stress and its controllability were cross-sectional associated with reduced, negative believes about stress however with enhanced associations between COVID-19-related work demands and burnout symptoms. This finding indicates, if confirmed by longitudinal research, the potential of the usage of stress beliefs in prevention programs for physicians in order to mitigating negative effects of chronic stress.

Establishment of a teaching hospital-based dementia consultation service for rurally-based regional district general hospitals.

Objective: The treatment of patients with dementia poses a considerable challenge to regional district general hospitals, particularly in rural areas. Here we report the establishment and initial evaluation of a dementia-specific consultation service provided by a teaching hospital-based Psychiatry Department to regional district general hospitals in surrounding smaller towns. Methods: The consultation service was provided to patients with pre-existing or newly suspected dementia, who were in acute hospital care for concurrent conditions. An evaluation of 61 consultations - 49 on-site and 12 via telemedicine - was performed to assess the needs of the participating hospitals and the specific nature of the referrals to the consultation service. Results: Suspected dementia or cognitive dysfunction was the primary reason for consultation requests (>50% of cases). Other common requests concerned suspected delirium, behavioral symptoms, and therapeutic recommendations. During the consultations, a diagnosis of dementia was reached in 52.5% of cases, with other common diagnoses including delirium and depression. Recommendations related to pharmacotherapy were given in 54.1% of consultations. Other recommendations included referral for outpatient neurological or psychiatric follow-up, further diagnostic assessment, or assessment in a memory clinic. Geriatric psychiatric inpatient treatment was recommended in only seven cases (11.5 %). Conclusion: Our initial evaluation demonstrates the feasibility of providing a dementia-specific consultation service in rural areas. The service has the potential to reduce acute transfers to inpatient geriatric psychiatry and enables older patients with dementia or delirium to be treated locally by helping and empowering rurally-based regional hospitals to manage these problems and associated complications.

Mimicking reactive high-valent diiron-µ2-oxo intermediates of nonheme enzymes by an iron tetracarbene complex.

The first diiron(iii,iv)-µ2-oxo tetracarbene complex is isolated and characterized by SC-XRD, UV/Vis, EPR, Evans' NMR and elemental analysis. CV indicates the presence of a transient high-valent diiron(iv)-µ2-oxo species. Its formation and decay is investigated via UV/Vis kinetics and NMR.

Fluorescent palladium(II) and platinum(II) NHC/1,2,3-triazole complexes: antiproliferative activity and selectivity against cancer cells.

Fluorescent Pd(ii) and Pt(ii) complexes bearing 4-methylene-7-methoxycoumarin (MMC) and 2,6-diispropylphenyl (Dipp) substituted NHC/1,2,3-triazole hybrid ligands are described. Depending on the reaction conditions two different ligand coordination modes are observed, i.e., bidentate solely coordinating via NHCs or tetradentate coordinating via NHCs and 1,2,3-triazoles. All Dipp substituted complexes show antiproliferative activity against cervix (HeLa) and breast (MCF-7) human carcinoma cells. The activity significantly depends on the coordination mode, with the tetradentate motif being notably more effective (HeLa: IC50 = 3.9 µM to 4.7 µM; MCF-7: IC50 = 2.07 µM to 2.35 µM). Amongst the MMC series, only the Pd(ii) complex featuring the bidentate coordination mode is active against HeLa (IC50 = 6.1 µM). In contrast to its structurally related Dipp derivative (SI = 0.6), it shows a high selectivity for HeLa (SI > 16) compared to healthy skin cells (HaCaT). According to fluorescence microscopy, this compound is presumably located in late endosomes or lysosomes.

Gold(I) Bis(1,2,3-triazol-5-ylidene) Complexes as Promising Selective Anticancer Compounds.

The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC50 values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 µM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.

Genetic diversity in water frog hybrids (Pelophylax esculentus) varies with population structure and geographic location.

Pelophylax esculentus is a hybridogenetic frog originating from matings between P. ridibundus (RR) and P. lessonae (LL). Typically, diploid hybrids (LR) live in sympatry with one of their parental species, upon which they depend for successful reproduction. In parts of their range, however, pure hybrid populations can be found. These hybrid populations have achieved reproductive independence from their parental species by using triploid hybrids (LLR, LRR) rather than LL and RR as their sexual hosts. These different breeding systems also entail differences in reproduction (clonal versus sexual) and hence offer the opportunity to study how genetic diversity is affected by reproductive mode, population structure and geographic location. We investigated 33 populations in the Scania region (South Sweden) and 18 additional populations from Northern and Central Europe. Within both genomes (L, R), genetic variability increases with the potential for recombination and declines from the main species distribution area southeast of the Baltic Sea to the fringe populations northwest of the Baltic Sea. Within the main study area in Scania, genetic diversity is low and decreases from a core area to the periphery. Genetic differentiation between Scania populations is small but significant and best explained by 'isolation by distance'. Despite the low genetic variability within the discrete genomes, all-hybrid P. esculentus populations in southern Sweden are apparently not suffering from direct negative fitness effects. This is probably because of its somatic hybrid status, which increases diversity through the combination of genomes from two species.

BSc2118 is a novel proteasome inhibitor with activity against multiple myeloma.

OBJECTIVES: The ubiquitin-proteasome system emerged as a new therapeutic target in cancer treatment. The purpose of this study was to elucidate the effects of the novel proteasome inhibitor BSc2118 on t(4;14) positive and negative multiple myeloma (MM) cells and normal peripheral blood mononuclear cells (PBMNC). METHODS: Human MM cell lines OPM-2, RPMI-8226, and U266 and primary MM cells from bone marrow aspirates were exposed to BSc2118. Cytotoxicity levels were evaluated using the MTT-test. BSc2118-induced apoptosis was analyzed by annexin-V assay. Further methods used included proteasomal activity determination, cell cycle analysis, western blot, and transcription factor assays. RESULTS: In OPM-2, RPMI-8226, U266 cell lines and primary MM cells, BSc2118 caused dose-dependent growth inhibitory effects. After 48 h, dose-dependent apoptosis occurred both in cell lines and primary myeloma cells irrespective of t(4;14). A significant G2-M cell cycle arrest occurred after 24 h. Furthermore, we observed a marked inhibition of intracellular proteasome activity, an increase in intracellular p21 levels, and an inhibition of NF-kappaB activation. The toxicity against PBMNC remained low, suggesting a broad therapeutic range of this agent. CONCLUSION: Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development.

Synergistic interaction of proteasome and topoisomerase II inhibition in multiple myeloma.

Multiple myeloma is a malignancy of terminally differentiated plasma cells and is incurable in the majority of the patients. Thus, novel effective treatment regimens are urgently needed. In this study, we examined the effects of co-treatment with proteasome-inhibitor bortezomib and topoisomerase II inhibitor etoposide in multiple myeloma cells lines OPM-2, RPMI-S and NCI-H929. Using the median effect method of Chou and Talalay, we evaluated the combination indices (CI) for simultaneous and sequential treatment schedules. In the sequential treatment schedule, we found strong synergistic effects in all three cell lines, even at low single-agent cytotoxicity levels. When cells were treated simultaneously with both drugs, the synergy was present but less pronounced than in the sequential treatment schedule. The synergistic effects observed in the co-treatment schedules were accompanied by an inhibition of anti-apoptotic effects that were induced by etoposide alone. Namely, bortezomib abrogated both etoposide-induced NF-kappaB activation and etoposide-induced bcl-2 up-regulation. Our data suggest that combining etoposide with bortezomib might be useful for cancer treatment, as bortezomib potentially inhibits counter-regulatory mechanisms of tumor cells, which are induced by topoisomerase II inhibition and which may contribute to acquired chemoresistance.

Coexistence of diploid and triploid hybrid water frogs: population differences persist in the apparent absence of differential survival.

UNLABELLED: The role of differential selection in determining the geographic distribution of genotypes in hybrid systems has long been discussed, but not settled. The present study aims to asses the importance of selection in structuring all-hybrid Pelophylax esculentus populations. These populations, in which the parental species (P. lessonae with genotype LL and P. ridibundus with genotype RR) are absent, have pond-specific proportions of diploid (LR) and triploid (LLR and LRR) genotypes. RESULTS: With data from 12 Swedish ponds, we first show that in spite of significant changes in genotype proportions over time, the most extreme ponds retained their differences over a six year study period. The uneven distribution of genotypes among ponds could be a consequence of differential selection varying among ponds (selection hypothesis), or, alternatively, of different gamete production patterns among ponds (gamete pattern hypothesis). The selection hypothesis was tested in adults by a six year mark-recapture study in all 12 ponds. As the relative survival and proportion of LLR, LR and LRR did not correlate within ponds, this study provided no evidence for the selection hypothesis in adults. Then, both hypotheses were tested simultaneously in juvenile stages (eggs, tadpoles, metamorphs and one year old froglets) in three of the ponds. A gradual approach to adult genotype proportions through successive stages would support the selection hypotheses, whereas the presence of adult genotype proportions already at the egg stage would support the gamete pattern hypothesis. The result was a weak preference for the gamete pattern hypothesis. CONCLUSIONS: These results thus suggest that selection is of little importance for shaping genotype distributions of all-hybrid populations of P. esculentus, but further studies are needed for confirmation. Moreover, the study provided valuable data on genotype-specific body lengths, adult survival and sex ratios.

Dinuclear Gold(I) Complexes Bearing N,N'-Allyl-Bridged Bisimidazolylidene Ligands.

A novel N,N'-allyl-bridged bisimidazolium salt and a novel dinuclear Ag(I) and a Au(I) NHC complex are reported. Both metallacyclic complexes have a twisted structural shape due to the rigid allylic system and form two different isomers relating to the position of the double bonds. The allyl-group shows photoisomerisation, but no reactivity towards bases for the additional coordination of Pd(II).

Improved Antiproliferative Activity and Fluorescence of a Dinuclear Gold(I) Bisimidazolylidene Complex via Anthracene-Modification.

A straightforward modification route to obtain mono- and di-substituted anthroyl ester bridge functionalized dinuclear Au(I) bis-N-heterocyclic carbene complexes is presented. The functionalization can be achieved starting from a hydroxyl-functionalized ligand precursor followed by transmetallation of the corresponding Ag complex or via esterification of the hydroxyl-functionalized gold complex. The compounds are characterized by NMR-spectroscopy, ESI-MS, elemental analysis and SC-XRD. The mono-ester Au complex shows quantum yields around 18%. In contrast, the corresponding syn-di-ester Au complex, exhibits significantly lower quantum yields of around 8%. Due to insufficient water solubility of the di-ester, only the mono-ester complex has been tested regarding its antiproliferative activity against HeLa- (cervix) and MCF-7- (breast) cancer cell lines and a healthy fibroblast cell line (V79). IC50 values of 7.26 µM in the HeLa cell line and 7.92 µM in the MCF-7 cell line along with selectivity indices of 8.8 (HeLa) and 8.0 (MCF-7) are obtained. These selectivity indices are significantly higher than those obtained for the reference drugs cisplatin or auranofin.

Antiproliferative Activity of Functionalized Histidine-derived Au(I) bis-NHC Complexes for Bioconjugation.

A series of histidine derived Au(I) bis-NHC complexes bearing different ester, amide and carboxylic acid functionalities as well as wingtip substituents is synthesized and characterized. The stability in aqueous media, in vitro cytotoxicity in a set of cancer cell lines (MCF7, PC3 and A2780/A2780cisR) along with the cellular uptake are evaluated. Stability tests suggest hydrolysis of the ester within 8 h, which might lead to deactivation. Furthermore, the bis-NHC system shows a sufficient stability against cysteine and the thiol containing peptide GSH. The benzyl ester and amide show the highest activity comparable to the benchmark compound cisplatin, with the ester only displaying a slightly lower cytotoxicity than the amide. A cellular uptake study revealed that the benzyl ester and the amide could have different intracellular distribution profiles but both complexes induce perturbations of the cellular physiological processes. The simple modifiability and high stability of the complexes provides a promising system for upcoming post modifications to enable targeted cancer therapy.

Mechanisms underlying the cytotoxic activity of syn/anti-isomers of dinuclear Au(I) NHC complexes.

The syn- and anti-isomers of dinuclear Au(I) complexes of the type Au2(RLOH)(PF6)2 (R = isopropyl or mesityl) bearing 2-hydroxyethane-1,1-diyl-bridged bisimidazolylidene ligands were separated by reversed phase high performance liquid chromatography (HPLC) and characterized by NMR spectroscopy, elemental analysis, ESI mass spectrometry as well as single crystal X-ray diffraction analysis. Evaluation of the antiproliferative activity of the isolated isomers has shown very small difference in their cytotoxic behavior in various cancer cell lines. Additional counter-anion exchange (hexafluorophosphate to chloride) allows to increase the water solubility of synAu2(MesLOH)(PF6)2 and leads to higher antiproliferative activity when compared to the hexafluorophosphate-complex. Both isomers were treated with l-cysteine as nucleophilic thiol source and only the anti-isomer shows dissociation of one bisimidazolylidene ligand after 24 h. In the case of the syn-isomer, density functional theory calculations indicate a lower reactivity due to the higher steric hindrance of the N-substituents and additional hydrogen bond interaction, which prevents a nucleophilic attack. When the N-substituent is replaced by the bulkier mesityl group, both conformations remain unreactive and result to be the most cytotoxic complexes in the above-mentioned cancer cell lines. Interestingly, synAu2(MesLOH)(PF6)2 exhibits a high selectivity in the MCF-7 cell line with a selectivity index (SI) of 19, which is superior to auranofin (SI < 1), making this compound an ideal candidate for further studies. Preliminary mechanistic studies reveal that the cytotoxic complexes possess mitochondrial-TrxR inhibition properties in the nanomolar range. Additionally, the cellular distribution studies by ICP-MS and nuclear microscopy have shown that the compound accumulates in the membranes. These results suggest that the mitochondrial membrane is the main target for this type of dinuclear complexes, causing oxidative stress by inhibiting mitochondrial thioredoxin reductase.

Serum concentrations of DKK-1 decrease in patients with multiple myeloma responding to anti-myeloma treatment.

Lytic bone destruction is a hallmark of multiple myeloma (MM) and is because of an uncoupling of bone remodeling. Secretion of Dickkopf (DKK)-1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. In this study, the effect of different treatment regimens for MM on serum DKK-1 was evaluated and correlated with the response to treatment in 101 myeloma patients receiving bortezomib, thalidomide, lenalidomide, adriamycin and dexamethasone (AD) or high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT). At baseline, myeloma patients had increased serum DKK-1 as compared with patients with MGUS (mean 3786 pg/mL vs. 1993 pg/mL). There was no difference between previously untreated MM patients and patients at relapse. A significant decrease of DKK-1 after therapy was seen in the following groups: Bortezomib (4059 pg/mL vs. 1862 pg/mL, P = 0.016), lenalidomide (11837 pg/mL vs. 4374 pg/mL, P = 0.039), AD (1668 pg/mL vs. 1241 pg/mL, P = 0.016), and AD + HDCT + ASCT (2446 pg/mL vs. 1082 pg/mL, P = 0.001). Thalidomide led to a non-significant decrease in DKK-1 (1705 pg/mL vs. 1269 pg/mL, P = 0.081). Within all groups, a significant decrease of DKK-1 was only seen in responders (i.e. patients achieving complete remission or partial remission), but not in non-responders. We show for the first time that serum DKK-1 levels decrease in myeloma patients responding to treatment, irrespective of the regimen chosen. These data suggest that myeloma cells are the main source of circulating DKK-1 protein and provide a framework for clinical trials on anti-DKK-1 treatment in MM.

Detection of renal impairment as one specific comorbidity factor in multiple myeloma: multicenter study in 198 consecutive patients.

OBJECTIVES: Comorbidity factors have been reported in cancer patients to predict progression free survival (PFS) and overall survival (OS). Renal impairment (RI) is postulated as one negative prognostic factor in multiple myeloma (MM). The study aim was to detect the best way to define RI and the impact of different RI stages on MM outcome. METHODS: In this multicenter analysis, we determined RI [serum creatinine, estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) and Cockcroft-Gault] and other prognostic factors in 198 MM patients to ascertain their value on PFS and OS. RESULTS: Median serum creatinine was 0.9 mg/dL in all patients, whereas the eGFR - being decreased with a median of 80 mL/min/1.73 m(2)- allowed to detect early stages of RI. Via univariate analysis, we observed increasing hazard ratios (HRs) for impaired OS with deteriorating eGFR: with eGFR(MDRD)<90 and <30, HRs were 1.3 and 2.9, respectively. Multivariate analysis determined RI with eGFR<30 and <50 as well as age >59 yr as most important variables for OS. By incorporating eGFR<30 as the most relevant factor determined via multivariate analysis and beta(2)-microglobulin (beta(2)-MG) in a novel MM-risk score, we identified patients with significantly differing OS: median survival with 0, 1 or 2 risk factors were 71, 48, and 24 months, respectively. CONCLUSIONS: These findings demonstrate that RI is frequent in MM, best detected via eGFR determination and an important prognostic factor. eGFR in combination with beta(2)-MG allows definitive risk stratification with largely differing survival in MM.

Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma.

OBJECTIVES: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. So far, there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. METHODS: DKK-1 serum levels were quantified in 184 untreated MM patients and 33 monoclonal gammopathy of undetermined significance (MGUS) patients by ELISA, using a monoclonal anti-DKK-1 antibody. RESULTS: Serum DKK-1 was elevated in MM as compared with MGUS (mean 11 963 pg/mL vs. 1993 pg/mL; P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL vs. 15 209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL vs. 17 915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1-3 vs. >3 lesions: 3114 pg/mL vs. 3559 pg/mL vs. 24 068 pg/mL; P = 0.002). CONCLUSION: Using a large series of myeloma patients, we could show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, indicating that DKK-1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma.

OBJECTIVES: Mantle cell lymphoma (MCL) is an incurable B cell lymphoma, and novel treatment strategies are urgently needed. We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and--among other mechanisms--results in a reduced nuclear factor-kappa B (NF-kappaB) activity. HDACi promote histone acetylation, and also interfere with NF-kappaB signaling. METHODS: Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H2DCFDA. In addition, activated caspases, proteasome- and NF-kappaB activity were quantified. RESULTS: Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values <1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N-acetyl-L-cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-kappaB activity. CONCLUSIONS: This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL.