Purpose: The time course of serum prostate-specific antigen (PSA) response to photodynamic therapy (PDT) of prostate cancer was measured.
Experimental Design: Seventeen patients were treated in a ...phase I trial of motexafin lutetium-PDT. PDT dose was calculated in each patient as
the product of the ex vivo measured pre-PDT photosensitizer level and the in situ measured light dose. Serum PSA level was measured within 2 months before PDT (baseline), and at day 1; weeks 1 to 3; months
1, 2, and 3; months 4 to 6; and months 7 to 11 after PDT.
Results: At 24 hours after PDT, serum PSA increased by 98% ± 36% (mean ± SE) relative to baseline levels ( P = 0.007). When patients were dichotomized based on median PDT dose, those who received high PDT dose showed a 119% ± 52%
increase in PSA compared with a 54% ± 27% increase in patients treated at low PDT dose. Patients treated with high versus
low PDT dose showed a median biochemical delay of 82 versus 43 days ( P = 0.024), with biochemical delay defined as the length of time between PDT and a nonreversible increase in PSA to a value
greater than or equal to baseline.
Conclusions: Results show PDT to induce large, transient increases in serum PSA levels. Patients who experienced high PDT dose showed
greater short-term increase in PSA and a significantly more durable PSA response (biochemical delay). These data strongly
promote the need for individualized delivery of PDT dose and assessment of treatment effect in PDT of prostate cancer. Information
gained from such patient-specific measurements could facilitate the introduction of multiple PDT sessions in patients who
would benefit.
Rann of Kachchh (RoK) is a unique geoformation, which is exposed to dynamic environmental changes such as salinity, temperature, and nutrients throughout the year. In this study, the pooled mat ...sample was examined for the cyanobacterial community structure using culture-dependent and culture-independent approaches. Taxonomic profiling was studied using amplicon sequencing that revealed the enrichment of Pseudanabaenales and Oscillatoriales by QIIME and MG-RAST, respectively. Other abundant orders were represented by Chroococcales, Nostocales, and unclassified cyanobacteria by both approaches. Nine cyanobacterial cultures were isolated from mat samples showing 90–98% similarities with available sequences in GenBank. The culture-dependent study suggested that mat was dominated by cyanobacterial orders such as Oscillatoriales—filamentous and Chroococcales—unicellular. Our results from the culture-dependent approach also indicated that despite high similarities in gene sequences, six cyanobacteria fall into the separate clade in the phylogenetic analysis that could be signs of evolution due to an extreme environment. Cultured isolates are correlated well with abundant taxa from amplicon sequencing. Further, protein profiling was done specifically for phycobiliproteins which will be helpful to elucidate their roles in light harvesting and energy transfer mechanism in the unique environment of RoK.
In recent years, targeted agents have rapidly evolved as effective tools in the clinical management of a broad range of malignant diseases. These agents disrupt molecular mechanisms and signaling ...modules that drive the malignant phenotype in defined subsets of malignancies. Beyond the intended cellular targets crucial to tumor growth and progression, these agents also affect signal transduction in normal cells and tissues. The resulting adverse events and their clinical management continue to change, as newer agents with an ever-increasing target spectrum are developed. We provide a succinct overview of dermatologic toxicities arising from the targeting of receptor tyrosine kinases and downstream effectors. Emergent insights into the pathomechanisms involved and the use of this knowledge base to alleviate cutaneous adverse events are discussed.
Breast cancer remains the cancer with the highest mortality among women in the United States. Peptides derived from the oncogenic Tac1 gene (full transcript: βPPT-A) stimulate the proliferation of ...breast cancer cells (BCCs) via seven-transmembrane G protein-coupled neurokinin 1 (NK1) and NK2 receptors. The NK1 gene could generate full-length (NK1-FL) and truncated (NK1-Tr) transcripts. NK1-Tr lacks 100 residues in their cytoplasmic end, could couple to G proteins, and shows reduced efficiency with respect to internalization and desensitization. This study reports on a role of NK1-Tr in the transformation of nontumorigenic breast cells, and investigates whether Tad expression is linked to the generation of NK1-Tr. Western blots and Northern analyses showed coexpressions of NK1-Tr and NK1-FL in BCCs (cell lines and primary cells from patients with different stages of breast cancer). Stable transfections of βPPT-A or NK1-Tr expression vectors in nontumorigenic cells showed each induces the expression of the other, consequently resulting in a transformed phenotype. Analyses with microarrays indicate similar patterns of cytokine production by NK1-Tr transfectants and BCCs, but not NK1-FL transfectants. These observations indicate tumor-promoting properties by NK1-Tr, but not NK1-FL. Overall, the oncogenic property of Tac1 in breast cells involves concomitant expression of NK1-Tr and vice versa, consequently leading to the production of cytokines with growth promoting functions.
Context: Microcrystalline cellulose (MCC) is the most widely used excipient for the production of pellets but it retards the release of poorly water soluble drugs. Objective: The present ...investigation reports incorporation of camphor, cross carmellose sodium (CCS) and spray dried lactose (SDL) into MCC pellets to enhance the dissolution rate of telmisartan. Materials and methods: A full factorial design (32) was used in the study. Concentration of camphor and CCS was selected as independent variables whereas percentage porosity and percentage drug release at 60min were selected as dependent variables. Pellets were produced by extrusion–spheronization technique and evaluated for percentage yield, particle size analysis, flow characteristics, percentage porosity, drug content and in vitro drug release. Contour plots and 3-D surface plots were presented for graphical expression of the results. Results and discussion: Pellet formulations exhibited acceptable morphological, flow and mechanical properties. As against to 38.54% drug release after 60min with MCC pellets, pellets prepared with optimized formulation, composed of proper combination of MCC, SDL, camphor and CCS, released 100% drug after 60min. Conclusion: Our study underlines the fact that dissolution of telmisartan from MCC pellets can be successfully enhanced by incorporating water soluble excipient, disintegrant and pore formers.
BackgroundImmune-mediated diarrhea or colitis (IDC) is a potentially serious adverse event which can occur in up to 10% of patients receiving an immune checkpoint inhibitor (ICIs), but not all ...episodes of diarrhea among these patients are immune-mediated.1 There is a paucity of research regarding the diagnosis and management of this common symptom among patients receiving an ICI.MethodsWe collected retrospective clinical data for all patients who received at least one dose of an ICI for any cancer diagnosis (n=2,120) and subsequently underwent a diagnostic workup for acute diarrhea with stool testing for either C. difficile or a gastrointestinal pathogen panel (n=223) at any point between 1/1/13 to 3/17/21. We compared patients who had IDC “ruled out” to those who had confirmed IDC using Fisher's exact test for categorical variables and either independent samples t-test or Wilcoxon two-sample tests for interval variables. The Kaplan-Meier method was used to estimate progression-free and overall survival time. A two-sided alpha of 0.05 was utilized in determining which relationships might be significant.ResultsThirty-seven percent had ICIs deferred upon symptom onset, and 28% received systemic steroids. Patients receiving an ICI who developed diarrhea were 2.14x more likely to have a different etiology for their symptoms (n=152, 68%) than IDC. Patients who had IDC ruled out were more likely to be female (47%, p 0.029) and have at least one comorbidity (93%, p 0.028). Patients with confirmed IDC were more likely to have peptic ulcer disease (4%, p 0.031), to have received ipilimumab (24%, p<0.0001) or >1 ICI concurrently 23%, p<0.001), and to have a shorter time since last dose of immunotherapy to onset of symptoms (12 vs. 26 days, p <0.0001). There were no differences in age, race, ethnicity, prior cancer therapies, types of other comorbidities, symptoms, presence of other adverse events, number of ICI cycles prior to symptom onset, or performance status. Progression-free survival was longer among patients with confirmed IDC (p 0.003). Overall survival was longer among patients with confirmed IDC (p 0.021) (figure 1).ConclusionsDiarrhea is often due to another etiology besides IDC, especially among patients who have onset of symptoms over 2 weeks after receiving an ICI other than ipilimumab. If ipilimumab or two ICIs are used concurrently, it is warranted to have increased suspicion for IDC especially with rapid progression of symptoms. This dataset provides additional evidence that confirmed IDC may be associated with prolonged progression-free and overall survival.ReferenceWang Y, Zhou S, Yang F, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol 2019;5(7):1008–1019. doi:10.1001/jamaoncol.2019.0393Ethics ApprovalThe study was approved by Wake Forest Baptist Health Ethics Board, approval number #IRB00044126.Abstract 815 Figure 1Survival of confirmed IDC and ruled-out cases
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is the redox regulator of multiple stress-inducible transcription factors, such as NF-κB, and the major 5′-endonuclease in base ...excision repair (BER). We utilized mice containing a heterozygous gene-targeted deletion of APE1/Ref-1 (
Apex
+/−) to determine the impact of APE1/Ref-1 haploinsufficiency on the processing of oxidative DNA damage induced by 2-nitropropane (2-NP) in the liver tissue of mice. APE1/Ref-1 haploinsufficiency results in a significant decline in NF-κB DNA-binding activity in response to oxidative stress in liver. In addition, loss of APE1/Ref-1 increases the apoptotic response to oxidative stress, in which significant increases in GADD45g expression, p53 protein stability, and caspase activity are observed. Oxidative stress displays a differential impact on monofunctional (UNG) and bifunctional (OGG1) DNA glycosylase-initiated BER in the liver of
Apex
+/− mice. APE1/Ref-1 haploinsufficiency results in a significant decline in the repair of oxidized bases (e.g., 8-OHdG), whereas removal of uracil is increased in liver nuclear extracts of mice using an in vitro BER assay.
Apex
+/− mice exposed to 2-NP displayed a significant decline in 3′-OH-containing single-strand breaks and an increase in aldehydic lesions in their liver DNA, suggesting an accumulation of repair intermediates of failed bifunctional DNA glycosylase-initiated BER.
Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers ...with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear.
and
encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH.
Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting.
We discovered a novel missense variant in the
gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a
protein-truncating variant in the
. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h.
We have identified two rare novel variants in
and
using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.
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