Regeneration: The origin of cancer or a possible cure?

A better understanding of the forces controlling cell growth will be essential for developing effective therapies in regenerative medicine and cancer. Historically, the literature has linked cancer and tissue regeneration—proposing regeneration as both the source of cancer and a method to inhibit tumorigenesis. This review discusses two powerful regeneration models, the vertebrate urodele amphibians and invertebrate planarians, in light of cancer regulation. Urodele limb and eye lens regeneration is described, as well as the planarian's emergence as a molecular and genetic model system in which recent insights begin to molecularly dissect cancer and regeneration in adult tissues.     

HIV-1 remission and possible cure in a woman after haplo-cord blood transplant

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Management of extensively drug-resistant tuberculosis in Peru: cure is possible

Aim

To describe the incidence of extensive drug-resistant tuberculosis (XDR-TB) reported in the Peruvian National multidrug-resistant tuberculosis (MDR-TB) registry over a period of more than ten years and present the treatment outcomes for a cohort of these patients.

Methods

From the Peruvian MDR-TB registry we extracted all entries that were approved for second-line anti-TB treatment between January 1997 and June of 2007 and that had Drug Susceptibility Test (DST) results indicating resistance to both rifampicin and isoniazid (i.e. MDR-TB) in addition to results for at least one fluoroquinolone and one second-line injectable (amikacin, capreomycin and kanamycin).

Results

Of 1,989 confirmed MDR-TB cases with second-line DSTs, 119(6.0%) XDR-TB cases were detected between January 1997 and June of 2007. Lima and its metropolitan area account for 91% of cases, a distribution statistically similar to that of MDR-TB. A total of 43 XDR-TB cases were included in the cohort analysis, 37 of them received ITR. Of these, 17(46%) were cured, 8(22%) died and 11(30%) either failed or defaulted treatment. Of the 14 XDR-TB patients diagnosed as such before ITR treatment initiation, 10 (71%) were cured and the median conversion time was 2 months.

Conclusion

In the Peruvian context, with long experience in treating MDR-TB and low HIV burden, although the overall cure rate was poor, a large proportion of XDR-TB patients can be cured if DST to second-line drugs is performed early and treatment is delivered according to the WHO Guidelines.     

Apoptosis in cancer: cause and cure

The accumulation of neoplastic cells can occur through enhanced proliferation, diminished cell turnover, or a combination of both processes. Although the potential contribution of diminished cell turnover to tumor development has been appreciated for a decade, more recent studies in animal models and clinical cancer specimens have elucidated the mechanisms by which alterations in the apoptotic machinery contribute to the process of carcinogenesis. At the same time, a different group of studies have demonstrated the feasibility of eliminating neoplastic cells by selectively inducing apoptosis. In this essay, we review recent developments in the fields of carcinogenesis and molecular therapeutics in light of new understanding of apoptotic pathways.     

Enucleation: a possible mechanism of cancer cell death

There are few major morphologies of cell death that have been described so far: apoptosis (type I), cell death associated with autophagy (type II), necrosis (type III) and anchorage‐dependent mechanisms—anoikis. Here, we show for the first time a possibly novel mechanism inducing tumour cell death under in vitro conditions—enucleation. We pursued the influence of colloidal suspensions of Fe₃O₄ nanoparticles on tumour cell lines (SK‐BR‐3 and MCF‐7 breast cancer cell lines) grown according to standard cell culture protocols. Magnetite nanoparticles were prepared by combustion synthesis and double layer coated with oleic acid. Scanning and transmission electron microscopy revealed that tumour cells developed a network of intracytoplasmic stress fibres, which induce extrusion of nuclei, and enucleated cells die. Normal adult mesenchymal stem cells, used as control, did not exhibit the same behaviour. Intact nuclei were found in culture supernatant of tumour cells, and were visualized by immunofluorescence. Enucleation as a potential mechanism of tumour cell death might open new horizons in cancer biology research and development of therapeutic agents capable of exploiting this behaviour.     

Nonparametric estimation in a cure model with random cure times

Acute respiratory distress syndrome (ARDS) is a life-threatening acute condition that sometimes follows pneumonia or surgery. Patients who recover and leave the hospital are considered to have been cured at the time they leave the hospital. These data differ from typical data in which cure is a possibility: death times are not observed for patients who are cured and cure times are observed and vary among patients. Here we apply a competing risks model to these data and show it to be equivalent to a mixture model, the more common approach for cure data. Further, we derive an estimator for the variance of the cumulative incidence function from the competing risks model, and thus for the cure rate, based on elementary calculations. We compare our variance estimator to Gray's (1988, Annals of Statistics 16, 1140-1154) estimator, which is based on counting process theory. We find our estimator to be slightly more accurate in small samples. We apply these results to data from an ARDS clinical trial.     

Tumor-associated carbohydrate antigens: a possible avenue for cancer prevention

Here we examine the use of glycopeptides containing tumour-associated carbohydrate antigens (TACA) as potential preventive vaccines for carcinomas. Our recent results suggest that CD8+ T cells (CTL) are capable of recognizing TACA in a conventional class I MHC-restricted fashion. The ThomsenFriedenreich antigen (TF), a disaccharide, and Tn, its immediate precursor, are TACA largely expressed in carcinomas. TF and Tn can be successfully used as Th-independent vaccines when conjugated to designer peptides with optimal binding affinity for class I MHC molecules. TF- and Tn-specific CTL generated using this strategy are capable of recognizing TACA-expressing tumours in vitro, suggesting that glycopeptides are as effectively presented by class I MHC molecules as non-glycosylated peptides. Because the exact sequences of endogenously synthesized glycopeptides are unknown, the TACA-specific T cell repertoire elicited by carbohydrate-based vaccines is assumed to be degenerate. Here we report that mice genetically manipulated to develop TACA-expressing mammary tumours are not tolerant to glycopeptide vaccination. Moreover, we tested the immunogenicity of designer glycopeptides capable of binding multiple HLA alleles as a novel approach for the development of vaccines potentially useful for vaccination of a large fraction of the general population. Our results have suggested that CTL derived from normal donors respond with high efficiency to glycopeptides in vitro, opening a new avenue for the design of prospective vaccines for cancer prevention.     

The hypoxic core: a possible answer to the cancer paradox

There are many differences, at all levels of organization, between cancerous and normal cells. Two of these (oxygen delivery and glucose metabolism) are related and manifest as low intercellular oxygen tensions (pO(2)) and a glycolytic metabolic profile in tumours and/or cancer cells. It is becoming increasingly apparent that these characteristics of cancer combine to enhance both the survival and aggressiveness of cancer cells, and that they can adversely impact on some forms of treatment. But they are also exploited in current strategies of detection and monitoring of cancers. These are therefore characteristics with important implications for the crucial balance between the aggression and growth characteristics of a tumour, and our ability to detect and treat it. The interactions and the hierarchy of events leading to these manifestations are complex, not fully understood, and involve a pivotal and intriguing paradox. This paradox results in a seemingly contradictory state in which the most dangerous tumours are those that are the most hypoxic, but also those that are the most angiogenic. This review is a synthesis of the available data into a feasible hypothesis which offers a possible resolution of this paradox and provides a testable paradigm for tumour behaviour.     

Metformin and statins: a possible role in high-risk prostate cancer

Aim and backgroundThere is increasing evidence that statins and oral anti-diabetic drugs, such as metformin, can have a favorable role in advanced prostate cancer treatment.Metformin has been shown to inhibit proliferation of tumor cells in vitro and statins inhibit carcinogenesis by suppressing angiogenesis/invasion mechanisms. However, clinical evidence on the protective effect of these drugs is still weak.The purpose of this study is to analyze if these drugs have an impact on Biochemical-Failure-Free-Survival (BFFS) and on Distant-Failure-Free-Survival (DFFS) in localized high-risk prostate cancer.Material and MethodsFrom 2002–2016, 447 patients with histologically confirmed high-risk prostate cancer were retrospectively evaluated. All patients received radiotherapy and androgen deprivation therapy. Biochemical recurrence was determined by the Phoenix criteria and metastatic patients were defined by the presence of radiological metastasis. Survival analysis was performed using the Kaplan-Meier method.Results175 patients were treated with statins (65.3 % with a dose ≤ 20 mg/day) and 70 with metformin (75.7 % with a dose ≤ 1700 mg/day). Median follow-up was 88 months (1–194) with no differences in BFFS and DFFS between metformin and non-metformin patients (77.4 % versus 80 %, p = 0.91 and 89.4 % versus 88.7 %, p = 0.56, respectively). We did not find a statistical difference in BFFS and DFFS in patients taking higher doses of those drugs.ConclusionMetformin and statins were not associated with BFFS or DFFS improvement in our analysis. However, the small number of patients treated with these drugs limits the reliability of the results and prospective studies are needed.     

Using the canine genome to cure cancer and other diseases

A high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms, has been reported. Such new tools offer scientists amazing opportunities to define genetic, nutritional, environmental, and other risk factors for various canine diseases. Because many of the diseases that affect man's best friend also affect us, understanding a dog's disease may lead to new preventions and therapies for diseases that affect both dogs and people. Since a dog's life span is shorter than that for a human, monitoring potential risk factors in a well-controlled population of dogs is possible. Such a population should be one where dogs live in close relationship with their owners. Although longitudinal studies have been previously conducted on animals housed in laboratory environments, the natural environment offers a chance to study dogs in environments shared by their owners. If dogs are carefully monitored, and select exposures defined, considerable information could be collected in a dog's lifetime--the next 10-20 years. Such information could hold the clues for important discoveries, including causes and cures for cancer.