Nickel (II)-induced cytotoxicity and apoptosis in human proximal tubule cells through a ROS- and mitochondria-mediated pathway

Nickel compounds are known to be toxic and carcinogenic in kidney and lung. In this present study, we investigated the roles of reactive oxygen species (ROS) and mitochondria in nickel (II) acetate-induced cytotoxicity and apoptosis in the HK-2 human renal cell line. The results showed that the cytotoxic effects of nickel (II) involved significant cell death and DNA damage. Nickel (II) increased the generation of ROS and induced a noticeable reduction of mitochondrial membrane potential (MMP). Analysis of the sub-G1 phase showed a significant increase in apoptosis in HK-2 cells after nickel (II) treatment. Pretreatment with N-acetylcysteine (NAC) not only inhibited nickel (II)-induced cell death and DNA damage, but also significantly prevented nickel (II)-induced loss of MMP and apoptosis. Cell apoptosis triggered by nickel (II) was characterized by the reduced protein expression of Bcl-2 and Bcl-xL and the induced the protein expression of Bad, Bcl-Xs, Bax, cytochrome c and caspases 9, 3 and 6. The regulation of the expression of Bcl-2-family proteins, the release of cytochrome c and the activation of caspases 9, 3 and 6 were inhibited in the presence of NAC. These results suggest that nickel (II) induces cytotoxicity and apoptosis in HK-2 cells via ROS generation and that the mitochondria-mediated apoptotic signaling pathway may be involved in the positive regulation of nickel (II)-induced renal cytotoxicity.     

Synthesis and biological evaluation of 2-amino-1-thiazolyl imidazoles as orally active anticancer agents

Designed from a high throughput screened hit compound, novel 2-amino-1-thiazolyl imidazoles were synthesized and demonstrated cytotoxicity against human cancer cells. 1-(4-Phenylthiazol-2-yl)-4-(thiophen-2-yl)-1H-imidazol-2-amine (compound 2), a 2-amino-1-thiazolyl imidazole, inhibited tubulin polymerization, interacted with the colchicine-binding sites of tubulins, and caused cell cycle arrest at the G(2)/M phase in human gastric cancer cells. Disruption of the microtubule structure in cancer cells by compound 2 was also observed. Compound 2 concentration-dependently inhibited the proliferation of cancer cells in histocultured human gastric and colorectal tumors. Given orally, compound 2 prolonged the lifespans of leukemia mice intraperitoneally inoculated with the murine P388 leukemic cells. We report 2-amino-1-thiazolyl imidazoles as a novel class of orally active microtubule-destabilizing anticancer agents.     

A phase I and pharmacokinetic study of liposomal vinorelbine in patients with advanced solid tumor

Purpose This phase I study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of an untargeted liposomal formulation of vinorelbine (NanoVNB?) and to characterize its plasma pharmacokinetics in patients with advanced solid tumors which were refractory to conventional treatment or without an effective treatment. Patients & methods The study incorporated an accelerated titration design. Twenty-two patients with various solid tumors were enrolled. NanoVNB^? was administered intravenously at doses of 2.2–23 mg/m² once every 14 days. Pharmacokinetic endpoints were evaluated in the first cycle. The safety profiles and anti-tumor effects of NanoVNB? were also determined. Results Skin rash was the DLT and the most common non-hematological toxicity. The MTD was 18.5 mg/m². Drug-related grade 3–4 hematological toxicities were infrequent. Compared with intravenous free vinorelbine, NanoVNB? showed a high C_max and low plasma clearance. Of the 11 patients completing at least 1 post-treatment tumor assessment, 5 had stable disease. No responders were noted. Conclusion NanoVNB? was well tolerated and exhibited more favorable pharmacokinetic profiles than free vinorelbine. Based on dose-limiting skin toxicity, further evaluation of NanoVNB? starting from 18.5 mg/m² as a single agent or in combination with other chemotherapeutic agents for vinorelbine-active malignancies is warranted.     

Somatic mutations of the mitochondrial genome in human breast cancers

Somatic mutations in mitochondrial DNA (mtDNA) have been identified in various tumors, including breast cancer. However, their clinicopathological impact on breast cancer still remains unclear. In this study, we re-sequenced the entire mtDNA from breast cancer samples together with paired non-tumorous breast tissues from 58 Taiwanese patients. We identified 19 somatic mutations in the mtDNA coding region of 16 breast cancers. Out of these mutations, 12 of the 19 mutations (63%) are missense or frame-shift mutations that have the potential to cause mitochondrial dysfunction. In combination with our previously study on the D-loop region of mtDNA, we found that 47% (27/58) of the breast cancers harbored somatic mtDNA mutations. Among a total of 40 somatic mutations, 53% (21/40) were located in the D-loop region of the mtDNA, 5% (2/40) were in the ribosomal RNA genes, 5% (2/40) were in the tRNA genes, and 38% (15/40) occurred in mRNA genes. The occurrence of these somatic mtDNA mutations is associated with an older onset age (≥ 50-year old, P = 0.039), a higher TNM stage (P = 0.027), and a higher histological grade (P = 0.012). Multiple logistic regression analysis revealed that an older onset age (P = 0.029) and a higher histological grade (P = 0.006) are significantly correlated with patients having somatic mutations in the mtDNA in their breast cancer sample. In conclusion, our results suggest that somatic mtDNA mutations may play a critical role in the progression of breast cancer.     

A comparison of discharge functional status after rehabilitation in skilled nursing, home health, and medical rehabilitation settings for patients after lower-extremity joint replacement surgery

Mallinson TR, Bateman J, Tseng H-Y, Manheim L, Almagor O, Deutsch A, Heinemann AW. A comparison of discharge functional status after rehabilitation in skilled nursing, home health, and medical rehabilitation settings for patients after lower-extremity joint replacement surgery.

Objective

To examine differences in outcomes of patients after lower-extremity joint replacement across 3 post–acute care (PAC) rehabilitation settings.

Design

Prospective observational cohort study.

Setting

Skilled nursing facilities (SNFs; n=5), inpatient rehabilitation facilities (IRFs; n=4), and home health agencies (HHAs; n=6) from 11 states.

Participants

Patients with total knee (n=146) or total hip replacement (n=84) not related to traumatic injury.

Interventions

None.

Main Outcome Measure

Self-care and mobility status at PAC discharge measured by using the Inpatient Rehabilitation Facility Patient Assessment Instrument.

Results

Based on our study sample, HHA patients were significantly less dependent than SNF and IRF patients at admission and discharge in self-care and mobility. IRF and SNF patients had similar mobility levels at admission and discharge and similar self-care at admission, but SNF patients were more independent in self-care at discharge. After controlling for differences in patient severity and length of stay in multivariate analyses, HHA setting was not a significant predictor of self-care discharge status, suggesting that HHA patients were less medically complex than SNF and IRF patients. IRF patients were more dependent in discharge self-care even after controlling for severity. For the full discharge mobility regression model, urinary incontinence was the only significant covariate.

Conclusions

For the patients in our U.S.-based study, direct discharge to home with home care was the optimal strategy for patients after total joint replacement surgery who were healthy and had social support. For sicker patients, availability of 24-hour medical and nursing care may be needed, but intensive therapy services did not seem to provide additional improvement in functional recovery in these patients.     

Predicting treatment outcomes and responder subsets in scleroderma‐related interstitial lung disease

Objective

To identify baseline characteristics of patients with scleroderma‐related interstitial lung disease (SSc‐ILD) that could serve as predictors of the most favorable response to 12‐month treatment with oral cyclophosphamide (CYC).

Methods

Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in forced vital capacity (FVC) (% predicted values) and the placebo‐adjusted change in % predicted FVC over time (the CYC treatment effect).

Results

Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo‐adjusted improvement in the % predicted FVC of 2.11% at 12 months, which increased to 4.16% when patients were followed up for another 6 months (P = 0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates (assessed as maximum fibrosis scores) on high‐resolution computed tomography (HRCT) at baseline, the modified Rodnan skin thickness score (MRSS) at baseline, and the Mahler baseline dyspnea index as independent correlates of treatment response. When patients were stratified on the basis of whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or whether patients exhibited an MRSS of at least 23, a subgroup of patients emerged in whom there was an average CYC treatment effect of 9.81% at 18 months (P < 0.001). Conversely, there was no treatment effect (a −0.58% difference) in patients with less severe HRCT findings and a lower MRSS at baseline.

Conclusion

A retrospective analysis of the Scleroderma Lung Study data identified the severity of reticular infiltrates on baseline HRCT and the baseline MRSS as patient features that might be predictive of responsiveness to CYC therapy.

     

Treatment guidelines for acute and preventive treatment of cluster headache

The Treatment Guideline Subcommittee of the Taiwan Headache Society evaluated both the acute and the preventive treatments for cluster headache now being used in Taiwan, based on the principles of evidence- based medicine. We assessed the quality of clinical trials and levels of evidence, and referred to other treatment guidelines proposed by other countries. Throughout several panel discussions, we merged opinions from the subcommittee members and proposed a consensus on the major roles, recommended levels, clinical efficacy, adverse events and cautions of clinical practice regarding acute and preventive treatments of cluster headache. The majority of Taiwanese patients have episodic cluster headaches, because chronic clusters are very rare. Cluster headache is characterized by severe and excruciating pain which develops within a short time and is associated with ipsilateral autonomic symptoms. Therefore, emergency treatment for a cluster headache attack is extremely important. Within the group of acute medications currently available in Taiwan, the subcommittee determined that high-flow oxygen inhalation has the best evidence of effectiveness, followed by intranasal triptans. Both are recommended as first-line medical treatments for acute attacks. Oral triptans were determined to be second-line medications. For transitional prophylaxis, oral corticosteroids are recommended as the first-line medication, and ergotamine as the second-line choice. As for maintenance prophylaxis, verapamil has the best evidence and is recommended as the first-line medication. Lithium, melatonin, valproic acid, topiramate and gabapentin are suggested as the second-line preventive medications. Surgical interventions, including occipital nerve stimulation, deep brain stimulation, radiofrequency block of the sphenopalatine ganglion, percutaneous radiofrequency rhizotomy and trigeminal nerve section, are invasive and their long-term efficacy and adverse events are still not clear in Taiwanese patients; therefore, they are not recommended currently by the subcommittee. The transitional and maintenance prophylactic medications can be used together to attain treatment efficacy. Once the maintenance prophylaxis achieves efficacy, the transitional prophylactic medications can be tapered gradually. We suggest the corticosteroids be used within two weeks, if possible. The duration of maintenance treatment depends on the individual patient's clinical condition, and the medications can be tapered off when the cluster period is over.