Disrupting Na⁺, HCO3⁻-cotransporter NBCn1 (Slc4a7) delays murine breast cancer development.

Increased metabolism and insufficient blood supply cause acidic waste product accumulation in solid cancers. During carcinogenesis, cellular acid extrusion is upregulated but the underlying molecular mechanisms and their consequences for cancer growth and progression have not been established. Genome-wide association studies have indicated a possible link between the Na⁺, HCO3⁻-cotransporter NBCn1 (SLC4A7) and breast cancer. We tested the functional consequences of NBCn1 knockout (KO) for breast cancer development. NBCn1 protein expression increased 2.5-fold during breast carcinogenesis and was responsible for the increased net acid extrusion and alkaline intracellular pH of breast cancer compared with normal breast tissue. Genetic disruption of NBCn1 delayed breast cancer development: tumor latency was ~50% increased while tumor growth rate was ~65% reduced in NBCn1 KO compared with wild-type (WT) mice. Breast cancer histopathology in NBCn1 KO mice differed from that in WT mice and included less aggressive tumor types. The extracellular tumor microenvironment in NBCn1 KO mice contained higher concentrations of glucose and lower concentrations of lactate than that in WT mice. Independently of NBCn1 genotype, the cleaved fraction of poly(ADP-ribose) polymerase (PARP)-1 and expression of monocarboxylate transporter (MCT)1 increased while phosphorylation of Akt and ERK1 decreased as functions of tumor volume. Cell proliferation, evaluated from Ki-67 and phospho-histone H3staining, was ~60% lower in breast cancer of NBCn1 KO than that of WT mice when corrected for variations in tumor size. We conclude that NBCn1 facilitates acid extrusion from breast cancer tissue, maintains the alkaline intracellular environment and promotes aggressive cancer development and growth.

Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study.

Between October 1979 and May 1985, 626 patients with pharynx and larynx carcinoma were randomized to two different split-course radiation regimens and given either misonidazole (MISO; 11 g/m2) or placebo during the initial 4 weeks of treatment. Patients in the different treatment groups were evenly distributed among stages. The small number of females (136) gave an uneven distribution, thus making analysis difficult. The results show that females had a statistically better loco-regional control (45 vs. 33%; 5-year actuarial value). Overall, the MISO treated group did not have a significantly better control rate than the placebo groups (37 vs. 34%). However, a difference was found in patients with pharynx carcinomas (38 vs. 27%; p less than 0.05). The pre-irradiation hemoglobin (Hb) concentration was found to be a prognostic parameter. In females, loco-regional control for IIb values below or above 8 mmol/l were 37 and 47%, respectively. In males, the same values were below or above 9 mmol/l 26 and 38%. Hb influence on local control was only seen in supraglottic and pharynx tumors. This effect was independent of tumor size, which also was of prognostic value. In addition Hb concentration and MISO had an apparent additive effect. Thus in the male pharynx group, placebo patients with low Hb had a 14% disease rate compared to 40% in MISO treated patients with Hb above 9 mmol/l. MISO induced significant peripheral neuropathy in 26% of the treated patients, whereas other drug related side effects were minimal and tolerable.

Irradiation, chemotherapy and surgery in esophageal cancer: a randomized clinical study. The first Scandinavian trial in esophageal cancer.

In a randomized trial, irradiation alone (35 Gy) or irradiation (30 Gy) and bleomycin was given as preoperative treatment of esophageal cancer. In inoperable patients, a split course of irradiation alone (63 Gy) or irradiation (55 Gy) and bleomycin was given. Bleomycin doses were 5 mg i.m. 1/2-1 h before each irradiation dose. No benefit was obtained by addition of bleomycin to irradiation concerning survival or palliation of dysphagia. No benefit of bleomycin was seen either in any subgroup of patients according to different primary tumour classifications, histopathological gradings or localizations of tumour. In patients with advanced/metastatic disease, bleomycin and adriamycin treatment gave a significantly longer survival than bleomycin alone. It was shown that the presence of T1 tumours was a significant prognostic factor for long-term survival and that performing a radical operation was a significant advantage for a longer survival. Female patients treated with irradiation with or without bleomycin survived significantly longer than males, but in operable patients there was no significant difference between the two sexes with regard to survival.

Obstructive sleep apnea initiated by a lax epiglottis. A contraindication for continuous positive airway pressure.

Treatment with nasal continuous positive airway pressure (CPAP) was attempted in a patient with severe obstructive sleep apnea. However, application of nasal CPAP gave the patient a feeling of being suffocated. This was later documented by cine-fluoroscopic examinations of the upper airways with and without nasal CPAP. The epiglottis was large and lax, and upon positive pressure inspiration, it was literally blown down so it occluded the hypopharyngeal airway.

Characteristics of dividing and non-dividing Tetrahymena cells at different physiological states.

Eight defined physiological states of Tetrahymena pyriformis are described. For dividing cells the states comprise: 1. Exponentially growing cells, 2. Cells at late exponential growth phase, 3. Cells kept at a high cell concentration, 4. Cells shifted up or down by change of medium, temperature or degree of aeration. For non-dividing cells the states are: 5. Cells at stationary phase, 6. Cells during starvation, 7. Cells during shift-up after long-term starvation, 8. Cells at self-induced hypoxia. The different cellular states are described by one or more of the following characteristics: growth rate, volume, swimming speed, oxygen consumption and by the oxygen saturation and the pH in the medium. The results show that T. pyriformis grows equally well in proteose-peptone (PY) medium from 1 cell ml(-1) to 10(3) cells ml(-1) as from - e.g. - 10(2) to 10(5) cells ml(-1). The maximum cell concentration obtained depends on the medium and the availability of oxygen. At shift-down by decrease of temperature the cells grow slower and obtain a considerable oversize. Single cells tolerate starvation for 12 days. The cell volume (electronically determined) decreased from about 7000 µm(3) to about 200 µm(3). Long-term starved cells may be upshifted. Thereby growth without cell division can be studied until the cell volume approaches 2100 µm(3) which is the minimum volume of division competence. Under certain conditions cells may grow into self-induced hypoxia leading to growth arrest. These cells will attain an oversize. The swimming speed at 28°C of exponentially growing cells is 0.33 to 0.59 mm sec(-1) depending on the medium. At lower temperature the swimming speed is decreased. In PY-medium the values are: 28°C (0.57), 16°C (0.50), 9°C (0.37). During starvation the swimming speed decreases from about 0.6 to about 0.1 mm sec(-1) (after 6 days). The oxygen consumption is for state 1 cells: 3.9 µl O(2)/10(6) cells min(-1) (maximal value). The value of hypoxic cultures is 2.1, for cells kept at high concentration 0.4, and for starved cells (24 h) 0.2.

Glomus jugulare tumours. (A series of 21 cases).

Twenty-one cases of glomus jugulare tumours were analysed in retrospect. Six had been treated surgically, ten by irradiation, and five by a combination of incomplete surgical excision followed by irradiation. Recurrences appeared in four cases, but no patient has died of the tumour during the follow-up period which is from a few months to eleven years. Metastases were not found in any case. The optimal time of irradiation in combined treatment is discussed.

Work potential evaluation in mental health.

A survey was conducted to describe the methods and the degree to which occupational therapists in mental health settings were evaluating the work potential of patients. Of the 231 responses received from a population of 500 therapists, 157 were usable for this study. Results showed that 36% of the respondents performed work potential evaluations using interest inventories, crafts, and miscellaneous nonstandardized measures as their primary sources of information, and they cited observation as the most useful tool to obtain information about a patient. Most respondents identified the need to do more in this area and expressed an interest in expanding their skills and available resources. Implications for occupational therapy were discussed in relationship to new Medicare legislation.

Postoperative irradiation of glioblastomas. Results in a randomized series.

A material of 108 patients with glioblastoma is presented. The series was randomized in two groups: cases only operated upon and cases with postoperative irradiation in addition. Patients dead within 2 months after operation were excluded in estimating the real value of the postoperative irradiation. The irradiated cases had a 6-month survival rate of 64 per cent and a one-year survival rate of 19 per cent; the non-irradiated cases a 6-month survival rate of 28 per cent and a one-year survival rate of 0 per cent.

Division competence in Tetrahymena: determination of minimum cell volume and rate of nutrient uptake.

Cell volume and doubling time have been determined for exponentially growing Tetrahymena pyriformis cells in broth medium with and without glucose and in media made from these media by dilution with water. The cells tolerate media with dry weights from 105 down to 0.06 g/L. In the diluted media the cells have small volumes and the doubling time is increased. When the cell volume increase per time per cell in a given medium is expressed as a function of the cell volume in this same medium, a direct proportionality is found. From this equation the minimum cell volume of division competence (MVDC) can be found. It is 2,100 microns 3 for T. pyriformis at 28 degrees C. The lag period resulting from an upshift of exponentially growing cells from diluted media to more concentrated media is a function of the initial and resulting cell volumes and MVDC. The increase in cell volume per unit of time for a given cell depends on the dry weight of the medium. This parameter can be transformed to mass increase per cell surface area per time, which represents rate of nutrient uptake. When plotted against the dry weight of the media, a Michaelis-Menten-like curve is obtained with two Km values of 3.8 and 0.08 g/L with corresponding Vmax values of 20 and 4 ng/cm2.s. The low Km value (0.08 g/L) indicates that Tetrahymena is able to take up nutrients from highly diluted media. The high value of Vmax (20 ng/cm2.s) increases the ability of growth in more concentrated media.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell volume and dry weight of cultured Tetrahymena.

Cultures of Tetrahymena pyriformis, T. hegewishi and T. malaccensis have been studied with regard to control of cell volume and cellular dry weight. Cell volume was measured on cells suspended in 0.9% sodium chloride + 0.1% sodium azide using a Multisizer cell counter (Coulter). Tetrahymena were grown at different temperatures and under various up- or downshift conditions. In all cases the changes in cell volume are paralleled by changes in cellular dry weight. The volume and the dry weight of a Tetrahymena cell are determined by the particular medium and the growth temperature. Large cells are seen in concentrated media and at low growth temperatures resulting in cell volumes up to 17,000 microns 3, whereas starving cells decrease gradually towards 700 microns 3 or even smaller sizes. It is proposed that lag phase observed at up- and downshift is to a large extent due to the necessary adjustment of the cell volume to the new conditions.