Cancer incidences in the digestive tube: is cobalamin a small intestine cytoprotector?

Malignancies are common in the digestive tube, although with unequal distribution among segments. The aim of this paper was to compare available interpretations of the low cancer incidence in the small bowel and high in the large bowel. Supposed mechanisms include relatively small bacterial population, large secretion of liquid and rapid transit in the small bowel. Small bowel mucosa is the main absorptive part of the digestive tube with absorption rates for various nutrients so high that they can even be considered as clearances from the intestinal content. Consequently, these nutrients are not present in the large bowel. An alternative explanation is that an absorbable protective substance from the intraluminal content, might protect the mucosa from malignant transformations. It can be speculated that if there are any cytoprotective substances in the digested food their effect would be expressed mostly in the absorptive small intestine, leaving the large bowel mucosa unprotected. Vitamin B12 might be a possible candidate for this role. Cobalamin molecules are initially bound to haptocorrin (Hc) in the stomach, but in the small intestine B12 is transferred to intrinsic factor (IF) after the action of pancreatic trypsin on Hc. Cobalamin-IF complexes are absorbed in the terminal ileum leaving only a small fraction of B12 to enter the large bowel. We have tried to summarize available data regarding cancer incidences in digestive tube, segmental length and transit times of tube content. Cancer density is calculated as incidence per length and transit speed as length per transit time. Cancer incidences for seven intestinal segments were considered low if they were below one case per 100 000 inhabitants annually, while the low cancer density meant less than six cases per 100 000 inhabitants per metre. For instance, transverse colon was considered as a high cancer incidence place (2.15 cases), with low cancer density (4.3 cases/m). Transit speed more than 0.3 metre/hour was associated with low cancer incidences (accuracy 0.85) and low cancer density segments (accuracy 1.00). Cobalamin availability showed similar distribution, available in low incidence segments and unavailable in high incidence segments. Experimental studies are needed to quantify B12 availability in the large bowel and to determine whether small amounts of B12-IF or, perhaps, B12-haptocorrin complexes are absorbed by the small bowel mucosa. Without that, no cytoprotective effects of B12 in the digestive tube can be expected.     

The role of radiation therapy in the treatment of metastatic cancer

Radiation therapy continues to play an important role in the management of cancer. In this review, we discuss the use of radiation therapy to target and control micrometastatic disease (adjuvant use of radiation), or using stereotactic radiation therapy to address small volumes of gross disease, such as oligometastases, and finally the use of radiation therapy in the era of immunotherapy. Radiation therapy is commonly used to treat nodal basins suspected of harboring microscopic disease. More recently, computer and technical innovations have allowed radiation oncologists to treat small volumes of gross disease within the brain and also in the body with great success, adding to the cancer armamentarium. This modality of cancer treatment that began shortly after the discovery of X-rays by William Roentgen continues to evolve and finds new clinical applications which minimize toxicity while increasing effectiveness. The newly discovered interactions of high dose/fraction radiation (stereotactic radiosurgery) with immune check point inhibitors in melanoma is the latest example of how synergism can be achieved between two different modalities thus increasing the therapeutic ratio to control metastatic cancer.     

The interactions of vanadium with Phycomyces blakesleeanus mycelium: enzymatic reduction,transport and metabolic effects

The biological and chemical basis of vanadium action and transport in fungi is relatively poorly understood. In this study we investigated the interactions of vanadium in physiologically-relevant redox states: vanadate (+5) and vanadyl (+4), with mycelium of fungus Phycomyces blakesleeanus using EPR and ³¹P NMR spectroscopy and biochemical assays. We determined that P. blakesleeanus reduces V⁵⁺ to V⁴⁺ in the extracellular compartment by the means of cell surface enzyme with ferricyanide reductase activity, which contains molybdenum–molybdopterin as a cofactor. Both, V⁵⁺ and V⁴⁺ bind to cell wall. They enter the cytoplasm via phosphate transporter and cation channels, respectively, and exhibit different metabolic effects. Vanadate provokes increased biomass production, the effects being inverted to toxic at higher V⁵⁺ concentrations. In addition, V⁵⁺ activates the synthesis of sugar phosphates and oligophosphates. On the other hand, V⁴⁺ exhibits toxic effects even at low concentrations. The V⁴⁺ detoxification route involves binding to vacuolar polyphosphates. Altogether our results imply that the mechanism of interaction of vanadium with P. blakesleeanus involves three major steps: extracellular enzymatic V⁵⁺/V⁴⁺ reduction, V⁴⁺ influx, and vacuolar storage, with an additional step – V⁵⁺ import occurring at higher vanadate concentrations.     

Fusarium: two endophytic novel species from tropical grasses of northern Australia

Two new species of Fusarium associated with Australian indigenous grasses in natural ecosystems are described as F. lyarnte and F. werrikimbe on the basis of morphology, DNA fingerprinting and phylogenetic analysis of EF-1α and β-tubulin sequence data. Isolates of these species were initially recovered from soil in the McGraths Creek area of central Australia and subsequently recovered from soil and stems of the indigenous grass Sorghum interjectum from Litchfield National Park in the Northern Territory, and from Sorghum leiocladum from Werrikimbe National Park in New South Wales. The common feature of both of these species is the production of large globose microconidia in false heads on polyphialides. Attempts to apply the biological species concept were unsuccessful.     

Blood lactate levels in patients receiving first- or second- generation antipsychotics

Aim

To compare the blood lactate levels between patients with psychotic disorder receiving first- and those receiving second-generation antipsychotics.

Methods

The study was conducted at the psychiatric inpatient and outpatient clinics of the Split Clinical Hospital from June 6, 2008 to October 10, 2009. Sixty patients with psychotic disorder who were assigned to 6-month treatment were divided in two groups: 30 received haloperidol (first generation antipsychotic) and 30 received olanzapine (second generation antipsychotic). Blood lactate levels, other metabolic parameters, and scores on the extrapyramidal symptom rating scale were assessed.

Results

Patients receiving haloperidol had significantly higher blood lactate levels than patients receiving olanzapine (P < 0.001). They also more frequently had parkinsonism, which was significantly correlated with both haloperidol treatment at 1 month (P < 0.001) and 6 months (P = 0.016) and olanzapine treatment at baseline (P = 0.016), 3 months (P = 0.019), and 6 months (P = 0.021). Also, patients receiving haloperidol had significant correlation between blood lactate and dystonia at 1 month (P < 0.001) and 6 months (P = 0.012) and tardive dyskinesia at 1 month (P = 0.032). There was a significant difference between the treatment groups in lactate levels at all points from baseline to month 6 (P < 0.001).

Conclusion

It is important to be aware of the potential effect of haloperidol treatment on increase in blood lactate levels and occurrence of extrapyramidal side effects. Therefore, alternative antipsychotics should be prescribed with lower risk of adverse side effects.

Trial identification number

NCT01139463Due to their heterogeneity, antipsychotics are difficult to classify, but they are frequently categorized as the first- and second-generation based on the incidence of extrapyramidal side effects, ie, antidopaminergic activity (1,2). First-generation antipsychotics have dominant antidopaminergic activity and pronounced extrapyramidal side effects (1), while second-generation antipsychotics have a pronounced effect on other neurotransmitter systems, as well as sporadic extrapyramidal side effects.Antipsychotics block numerous neurotransmitter receptors in a manner that induces therapeutic effects and side effects, which may vary in intensity and produce serious consequences (3-7). Extrapyramidal side effects (adverse cardiovascular, hematological, gastrointestinal, sexual, and urologic effects) are most frequently manifested in first-generation antipsychotics due to their non-selective dopaminergic block (1,8-10). The consequence of a dopaminergic effect on the tuberoinfundibular system causing dopamine to inhibit prolactin secretion is hyperprolactinemia (11,12), with possible consequences such as tissue hypoxia and mortality (13-15).Particular attention today is paid to the effects of first-generation antipsychotics on metabolic disorders. Numerous studies have shown that first-generation antipsychotic therapy may lead to metabolic changes, particularly changes in the regulation of glucose, lipid levels, and body weight (3-5,13-21). These side effects are associated with increased mortality and substantial morbidity including diabetes, hypertension, and cardiovascular disease (22,23). In many years of clinical practice, we have empirically observed that treatment with certain antipsychotics causes, along with recognized and described metabolic disorders, an increase in the blood lactate levels. Increased lactate levels are generally associated with increased morbidity and mortality in patients with chronic illnesses or critically ill patients (13,14,24-26). A review of the literature did not find any studies on the effect of antipsychotic therapy on lactate levels or such changes as a part of other antipsychotic side effects. Therefore, it is important to investigate this phenomenon in patients taking first- or second-generation antipsychotic medication.We hypothesized that a 6-month treatment with haloperidol or olanzapine would change blood lactate levels and cause extrapyramidal side effects in patients without prior antipsychotic treatment.     

Modeling the relationship between Higuchi’s fractal dimension and Fourier spectra of physiological signals

The exact mathematical relationship between FFT spectrum and fractal dimension (FD) of an experimentally recorded signal is not known. In this work, we tried to calculate signal FD directly from its Fourier amplitudes. First, dependence of Higuchi's FD of mathematical sinusoids on their individual frequencies was modeled with a two-parameter exponential function. Next, FD of a finite sum of sinusoids was found to be a weighted average of their FDs, weighting factors being their Fourier amplitudes raised to a fractal degree. Exponent dependence on frequency was modeled with exponential, power and logarithmic functions. A set of 280 EEG signals and Weierstrass functions were analyzed. Cross-validation was done within EEG signals and between them and Weierstrass functions. Exponential dependence of fractal exponents on frequency was found to be the most accurate. In this work, signal FD was for the first time expressed as a fractal weighted average of FD values of its Fourier components, also allowing researchers to perform direct estimation of signal fractal dimension from its FFT spectrum.     

MicroRNA-148b Targets the TGF-β Pathway to Regulate Angiogenesis and Endothelial-to-Mesenchymal Transition during Skin Wound Healing

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Genetic alterations in quadruple malignancies of a patient with multiple sclerosis: their role in malignancy development and response to therapy

Multiple cancers represent 2.42% of all human cancers and are mainly double or triple cancers. Many possible causes of multiple malignancies have been reported such as genetic alterations, exposure to anti-cancer chemotherapy, radiotherapy, immunosuppressive therapy and reduced immunologic response. We report a female patient with multiple sclerosis and quadruple cancers of different embryological origin. Patient was diagnosed with stage III (T3, N1a, MO) medullary thyroid carcinoma (MTC), multicentric micropapillary thyroid carcinoma, scapular and lumbar melanomas (Clark II, Breslow II), and lobular invasive breast carcinoma (T1a, NO, MO). All tumors present in our patient except micropapillary thyroid carcinomas were investigated for gene alterations known to have a key role in cancer promotion and progression. Tumor samples were screened for the p16 alterations (loss of heterozygosity and homozygous deletions), loss of heterozygosity of PTEN, p53 alterations (mutational status and loss of heterozygosity) and mutational status of RET, HRAS and KRAS. Each type of tumor investigated had specific pattern of analyzed genetic alterations. The most prominent genetic changes were mutual alterations in PTEN and p53 tumor suppressors present in breast cancer and two melanomas. These co-alterations could be crucial for promoting development of multiple malignancies. Moreover the insertion in 4^th codon of HRAS gene was common for all tumor types investigated. It represents frameshift mutation introducing stop codon at position 5 which prevents synthesis of a full-length protein. Since the inactivated RAS enhances sensitivity to tamoxifen and radiotherapy this genetic alteration could be considered as a good prognostic factor for this patient.