Tungsten disulfide nanotubes reinforced biodegradable polymers for bone tissue engineering

In this study, we have investigated the efficacy of inorganic nanotubes as reinforcing agents to improve the mechanical properties of poly(propylene fumarate) (PPF) composites as a function of nanomaterial loading concentration (0.01–0.2 wt.%). Tungsten disulfide nanotubes (WSNTs) were used as reinforcing agents in the experimental group. Single- and multi-walled carbon nanotubes (SWCNTs and MWCNTs) were used as positive controls, and crosslinked PPF composites were used as the baseline control. Mechanical testing (compression and three-point bending) shows a significant enhancement (up to 28–190%) in the mechanical properties (compressive modulus, compressive yield strength, flexural modulus and flexural yield strength) of WSNT-reinforced PPF nanocomposites compared to the baseline control. In comparison to the positive controls, significant improvements in the mechanical properties of WSNT nanocomposites were also observed at various concentrations. In general, the inorganic nanotubes (WSNTs) showed mechanical reinforcement better than (up to 127%) or equivalent to that of carbon nanotubes (SWCNTs and MWCNTs). Sol fraction analysis showed significant increases in the crosslinking density of PPF in the presence of WSNTs (0.01–0.2 wt.%). Transmission electron microscopy (TEM) analysis on thin sections of crosslinked nanocomposites showed the presence of WSNTs as individual nanotubes in the PPF matrix, whereas SWCNTs and MWCNTs existed as micron-sized aggregates. The trend in the surface area of nanostructures obtained by Brunauer–Emmett–Teller (BET) surface area analysis was SWCNTs > MWCNTs > WSNTs. The BET surface area analysis, TEM analysis and sol fraction analysis results taken together suggest that chemical composition (inorganic vs. carbon nanomaterials), the presence of functional groups (such as sulfide and oxysulfide) and individual dispersion of the nanomaterials in the polymer matrix (absence of aggregation of the reinforcing agent) are the key parameters affecting the mechanical properties of nanostructure-reinforced PPF composites and the reason for the observed increases in the mechanical properties compared to the baseline and positive controls.     

Design and Biological Evaluation of Furan/Pyrrole/Thiophene‐2‐carboxamide Derivatives as Efficient DNA GyraseB Inhibitors of Staphylococcus aureus

DNA topoisomerases are well‐validated targets in micro‐organisms. DNA gyraseB is one of the most important enzymes among them as per their clinical importance. In earlier study, a novel lead 4‐((4‐(furan‐2‐carboxamido)phenyl)amino)‐4‐oxobutanoic acid was identified as inhibitor against DNA gyraseB with an IC₅₀ of 12.88 ± 1.39 μm . Subsequently, analogues of this lead were developed and evaluated through in vitro assays and in vivo studies. Among the 24 analogues, compound 22 was found to be the top hit with an improved DNA gyraseB activity of 5.35 ± 0.61 μm , and the binding affinity of this compound was further ascertained biophysically through differential scanning fluorimetry. The most potent ligand did not show any signs of cardiotoxicity in zebra fish ether‐ago‐go‐related gene, ascertaining the safety profile of this series a breakthrough among the previously reported cardiotoxic gyraseB inhibitors.     

Wee1 is required to sustain ATR/Chk1 signaling upon replicative stress

The therapeutic efficacy of nucleoside analogues, e.g. gemcitabine, against cancer cells can be augmented by inhibitors of checkpoint kinases, including Wee1, ATR, and Chk1. We have compared the chemosensitizing effect of these inhibitors in cells derived from pancreatic cancer, a tumor entity where gemcitabine is part of the first-line therapeutic regimens, and in osteosarcoma-derived cells. As expected, all three inhibitors rendered cancer cells more sensitive to gemcitabine, but Wee1 inhibition proved to be particularly efficient in this context. Investigating the reasons for this potent sensitizing effect, we found that Wee1 inhibition or knockdown not only blocked Wee1 activity, but also reduced the activation of ATR/Chk1 in gemcitabine-treated cells. Combination of several inhibitors revealed that Wee1 inhibition requires Cyclin-dependent kinases 1 and 2 (Cdk1/2) and Polo-like kinase 1 (Plk1) to reduce ATR/Chk1 activity. Through activation of Cdks and Plk1, Wee1 inhibition reduces Claspin and CtIP levels, explaining the impairment in ATR/Chk1 activity. Taken together, these results confer a consistent signaling pathway reaching from Wee1 inhibition to impaired Chk1 activity, mechanistically dissecting how Wee1 inhibitors not only dysregulate cell cycle progression, but also enhance replicative stress and chemosensitivity towards nucleoside analogues.     

Mdm2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors

Pharmacological inhibition of the cell cycle regulatory kinase Wee1 represents a promising strategy to eliminate cancer cells. Wee1 inhibitors cooperate with chemotherapeutics, e. g. nucleoside analogues, pushing malignant cells from S phase towards premature mitosis and death. However, considerable toxicities are observed in preclinical and clinical trials. A high proportion of tumor cells can be distinguished from all other cells of a patient''s body by inactivating mutations in the tumor suppressor p53. Here we set out to develop an approach for the selective protection of p53-proficient cells against the cytotoxic effects of Wee1 inhibitors. We pretreated such cells with Nutlin-3a, a prototype inhibitor of the p53-antagonist Mdm2. The resulting transient cell cycle arrest effectively increased the survival of cells that were subsequently treated with combinations of the Wee1 inhibitor MK-1775 and/or the nucleoside analogue gemcitabine. In this constellation, Nutlin-3a reduced caspase activation and diminished the phosphorylation of Histone 2AX, an indicator of the DNA damage response. Both effects were strictly dependent on the presence of p53. Moreover, Nutlin pre-treatment reduced the fraction of cells that were undergoing premature mitosis in response to Wee1 inhibition. We conclude that the pre-activation of p53 through Mdm2 antagonists serves as a viable option to selectively protect p53-proficient cells against the cytotoxic effects of Wee1 inhibitors, especially when combined with a nucleoside analogue. Thus, Mdm2 antagonists might prove useful to avoid unwanted side effects of Wee1 inhibitors. On the other hand, when a tumor contains wild type p53, care should be taken not to induce its activity before applying Wee1 inhibitors.     

Tumor heterogeneity and cancer stem cell paradigm: Updates in concept,controversies and clinical relevance

Although tumor heterogeneity is widely accepted, the existence of cancer stem cells (CSCs) and their proposed role in tumor maintenance has always been challenged and remains a matter of debate. Recently, a path‐breaking chapter was added to this saga when three independent groups reported the in vivo existence of CSCs in brain, skin and intestinal tumors using lineage‐tracing and thus strengthens the CSC concept; even though certain fundamental caveats are always associated with lineage‐tracing approach. In principle, the CSC hypothesis proposes that similar to normal stem cells, CSCs maintain self renewal and multilineage differentiation property and are found at the central echelon of cellular hierarchy present within tumors. However, these cells differ from their normal counterpart by maintaining their malignant potential, alteration of genomic integrity, epigenetic identity and the expression of specific surface protein profiles. As CSCs are highly resistant to chemotherapeutics, they are thought to be a crucial factor involved in tumor relapse and superficially appear as the ultimate therapeutic target. However, even that is not the end; further complication is attributed by reports of bidirectional regeneration mechanism for CSCs, one from their self‐renewal capability and another from the recently proposed concept of dynamic equilibrium between CSCs and non‐CSCs via their interconversion. This phenomenon has currently added a new layer of complexity in understanding the biology of tumor heterogeneity. In‐spite of its associated controversies, this area has rapidly emerged as the center of attention for researchers and clinicians, because of the conceptual framework it provides towards devising new therapies.     

An experimetal evaluation of nephroprotective potential of Butea monosperma extract in albino rats

Objective:

The current work was aimed to evaluate the nephroprotective potential of Butea monosperma.

Materials and Methods:

Butea monosperma was collected from local forest of Jabalpur and extracted with ethanol. Healthy adult male Wistar albino rats between 5 and 6 months of age and weighing about 150-200 g were used for the study. Acute toxicity studies were performed to determine dose of extract. Nephrotoxicity was induced by gentamicin. Animals were divided in four groups in which first group served as positive control, second group as gentamicin treated toxic control; animals of group three and four were treated with Butea monosperma extract. Extract was administered to animals via oral route. Serum creatinine, serum urea, and blood urea nitrogen were estimated. Body weight was also determined. Histopathological studies were performed to access gross anatomical changes in animals.

Results:

The extract of Butea monosperma was found to be rich in flavonoids, polyphenolics, and alkaloids. Urine creatinine, serum urea, and blood urea nitrogen were found to be significantly (P < 0.001) increased in rats treated with only gentamicin; whereas, treatment with the ethanolic extract of leaf of Butea monosperma reversed the effect of gentamicin indicating nephroprotective activity.

Conclusion:

The present study revealed that ethanolic extract of Butea monosperma is a good source of phytochemicals. The phytoconstituents flavonoids, phenolics, and alkaloids present in the extracts may be responsible for antioxidant activity. By the virtue of antioxidant activity, Butea monosperma demonstrated nephroprotective activity.KEY WORDS: Butea monosperma, gentamicin, nephroprotective     

Haemodynamic consequences of recurrent insulin‐induced hypoglycaemia

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Autologous stem cell transplantation in first remission is associated with better progression-free survival in multiple myeloma

Autologous stem cell transplant (ASCT) is standard consolidation therapy in management of multiple myeloma (MM) patients. We reviewed records of all consecutive MM patients who underwent ASCT with high-dose melphalan at our center from year 2002 to 2016. A total of 141 ASCT were conducted (90 males and 51 females) with median age of 55 years (23–68 years). Median time from diagnosis to transplant was 7 months (3–79), with majority of patients underwent transplant in first remission, while 17 (12%) patients received transplant beyond first remission. Eighty-three percent patients obtained CR/VGPR post-ASCT. Transplant-related mortality was 2.1%. At a median follow up of 54 months, mean overall survival (OS) and progression-free survival (PFS) group were 128.3 months (95% C.I. 111.9–144.7 months) and 73.8 months (95% C.I. 57.7–89.9 months), respectively. On univariate analysis, OS was adversely affected by renal insufficiency (p?=?0.024), while OS was better with CR/VGPR post-ASCT (p?<?0.001) and lenalidomide maintenance therapy (p?=?0.009). PFS was affected by CR/VGPR pre-ASCT (p?=?0.021), CR/VGPR post-ASCT (p?<?0.001), and transplant in first remission (p?=?0.034). On multivariate analysis, lenalidomide maintenance (versus thalidomide) (p?=?0.007) and CR/VGPR response post-ASCT (p?=?0.0003) were found to be predictors for better OS and CR/VGPR response at transplant for better PFS (p?=?0.038). Transplant in first remission versus beyond first remission showed a trend for better PFS (p?=?0.073). Conclusion: Majority of patients obtained CR/VGPR post-ASCT. Longer PFS was seen with patients who were transplanted in first remission.     

Isosorbide Mononitrate a Nitric Oxide Donor: A Study of Its Efficacy and Safety as an Agent for Cervical Ripening

Objective

To study the efficacy and safety profile of isosorbide mononitrate (IMN) as an agent for cervical ripening.

Methodology

This study was conducted in the Department of Obstetrics and Gynecology, M Y Hospital & M G M Medical College Indore from September 2011 to February 2013. Pregnant women attending the antenatal clinics were screened for possible participation in the study after explaining the nature of the study. This study was conducted on 150 patients. An initial dose of 40 mg IMN was applied in the posterior vaginal fornix, and the same dose was repeated after 6 h. Cervical ripening was assessed by the change in Bishop Score 12 h after the initial application.

Results

In a study of 150 cases, mean maternal age was 22.2 ± 2.6 years (range 19–35 years) and mean gestational age was 40.5 ± 1.07 (range 40–42 weeks). 52 women were primigravidas, while 98 were multigravidas. The mean Bishop Score—before drug administration was 1.94 ± 1.3 (range 0–5), and mean fetal heart rate was 137 ± 6.2 bpm. The mean of Bishop scores before IMN administration was 1.94 ± 1.3, while mean of Bishop score after drug administration was 6.7 ± 2.2; mean difference was equal to 4.76. P value was equal to 0.0001. By conventional criteria, this difference is considered to be statistically significant. The mode of delivery 96 (64 %) delivered vaginally, while 54 (36 %) were delivered by Cesarean section. Mean Apgar score at 1 min was 8.2 ± 0.9 SD (range 7–10), while mean Apgar score at 5 min was 9.4 ± 0.6 (range 8–10). The only side effect noted was headache, and 30 cases (20 %) complained of headache.

Conclusion

IMN seems to be effective, safe, inexpensive, and well-tolerated agent for cervical ripening. It is cost effective and safe with minimal side effects.