Bacteria And Chemotherapy Resistance

Bacteria associated with tumors can mediate resistance the chemotherapy drugs. Thus controlling bacterial species in cancer can enhance the efficacy of chemotherapy.  

There is a general pattern emerging from recent research of the importance of bacteria to human other than the simple paradigm of "there's a bacteria infection, give antibiotics." Bacteria we normally carry with us - such as the gut microbiota - affect human health for better or worse, as chronicled at this blog in a number of posts; now we see that human cancer can be associated with bacteria that affect resistance to chemotherapy.

Targeting human-cancer-bacteria interactions seems like a fruitful area of future research.

Cancer Cell Drug Addiction

By United States: National Institutes of Health - http://www.nih.gov/about/discovery/chronicdiseases/cancer.htm, Public Domain, https://commons.wikimedia.org/w/index.php?curid=25303787

Interestingly, cancer cells can not only become resistant to chemotherapeutic treatments, they can even become "addicted" to the drugs, actually becoming dependent on the drugs for growth!  In that sense, the drug are actually at that point feeding further tumor growth, and removing the drug can cause cancer cell death.  The mechanisms behind this is not well understand, and identifying these mechanisms would be helpful for designing more optimal therapeutic approaches (including alternating therapy regimens).  New data suggest certain cell signaling pathways may be involved.  Stay tuned for further developments; this is an important story.  Abstract:

Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes'. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial-mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.

Mitochondria And Aging: Fruit Flies...And Perhaps Humans As Well

By André Karwath aka Aka - Own work, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=227170

The mitochondria are the “powerhouses” of the cell, and problems with mitochondria and mitochondrial function have been associated with a number of diseases and disorders. Increased levels of dysfunctional mitochondria have been linked to aging, and this study linked here shows that “middle-aged” Drosophila (fruit flies) tend to have more elongated, dysfunctional mitochondria. Upregulation if a gene called Drp-1 promotes fission of those aberrant mitochondria, which in turn enhances mitophagy (in simple terms: cellular “clean-up” of the dysfunctional mitochondria) and enhanced mitochondrial function.  This in turn has anti-aging effects in the flies. Now, the objective here is not to improve the health of aging fruit flies (which may or may not be a worthy goal on its own, depending on your perspective), but to apply these findings to the human case, and to see how further investigation into these findings can inform us about ant-aging strategies in humans. This is the basic science-human health link on full display.  Abstract:

The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that upregulating Drp1-a Dynamin-related protein that promotes mitochondrial fission-in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle. Promoting Drp1-mediated mitochondrial fission, in midlife, facilitates mitophagy and improves both mitochondrial respiratory function and proteostasis in aged flies. Finally, we show that autophagy is required for the anti-aging effects of midlife Drp1-mediated mitochondrial fission. Our findings indicate that interventions that promote mitochondrial fission could delay the onset of pathology and mortality in mammals when applied in midlife. Mitochondrial fission and fusion are important mechanisms to maintain mitochondrial function. Here, the authors report that middle-aged flies have more elongated, or 'hyper-fused' mitochondria, and show that induction of mitochondrial fission in midlife, but not in early life, extends the health and life of flies.

Insulin Analogs And Breast Cancer Risk

By Bakerstmd - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=39243250

Long-acting insulin analogs are used in the treatment of type 2 diabetes.  Given the possible effects of such drugs on cell signaling pathways, the cancer risk needs to be ascertained.  It has been shown that the drug glargine leads to increased risk of breast cancer for women with type 2 diabetes. Assuming various confounding variables were accounted for, this is a serious issue, and drug side effects always need to be considered when planning treatment.  Abstract:

Purpose The association between long-acting insulin analogs and increased breast cancer risk is uncertain, particularly with the short follow-up in previous studies. We assessed this risk long term in women with type 2 diabetes. Methods A population-based cohort of women 40 years or older, all of whom were treated with long-acting (glargine, detemir) or neutral protamine Hagedorn (NPH) insulin between 2002 and 2012, was formed using the United Kingdom's Clinical Practice Research Datalink. Women were followed until February 2015 or breast cancer diagnosis. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% CIs of incident breast cancer, comparing long-acting insulin analogs with NPH overall, as well as by duration and cumulative dose. Results The cohort included 22,395 women who received insulin treatment, with 321 incident breast cancer events occurring during up to 12 years of follow-up (incidence rate 3.3 per 1,000 person-years). Compared with NPH insulin, insulin glargine was associated with an increased risk of breast cancer (HR, 1.44; 95% CI, 1.11 to 1.85), mainly increasing 5 years after glargine initiation (HR, 2.23; 95% CI, 1.32 to 3.77) and after > 30 prescriptions (HR, 2.29; 95% CI, 1.26 to 4.16). The risk was particularly elevated among prior insulin users (HR, 1.53; 95% CI, 1.10 to 2.12) but not for new users, which included fewer patients and for which one cannot rule out an HR of 1.81. The risk associated with insulin detemir was not significantly elevated (HR, 1.17; 95% CI, 0.77 to 1.77). Conclusion Long-term use of insulin glargine is associated with an increased risk of breast cancer in women with type 2 diabetes. The risk associated with insulin detemir remains uncertain because there are fewer users of this insulin.

Protein- and fiber-packed meal

 

Another experiment today resulted in a pretty edible lunch. It was all done in a pan, in less than 20 minutes. The meal has egg whites that supply the protein, and plenty of fiber coming from an onion, peppers and beans.

Ingredients:
1 carton egg whites, 16 oz
1 can black beans (drained), 15 oz
2-3 peppers (any color), cut into small pieces
1 big sweet onion, peeled, cut thinly  
a few garlic cloves, crushed
hot pepper flakes
black pepper
paprika
salt
2 Tbsp olive oil

How to cook:
Pour the oil in a pan and soften the onion in it. Mix from time to time to prevent burning. I use a cover to keep the moisture in the veggies, so that they are steamed rather than fried. Add the peppers, cover and continue cooking until desired softness. Continue mixing occasionally.  

Add the crushed garlic and the beans. After a minute or less, add the carton of egg whites, salt and all other spices (i.e., the listed in the Ingredients section or any other spices you may prefer). Heat through and mix until the egg whites are cooked. Serve with a salad (cucumbers with garlic, olive oil and vinegar go well).

I dramatically reduced my cheese consumption these days. In old times, I would have sprinkled some feta cheese on the egg whites.  Now, to compensate for my salt craving, I simply use salt. Is salt that bad for you, watch the new video on my favorite YouTube Channel What I've learned.  Be careful, however: there is an association between high consumption of salt/salt-preserved foods and stomach cancer!

Gene Expression And veteran Suicide Attempts

Here is a study showing suicide attempts by veterans is linked to altered gene expression associated with several cell signaling pathways, including mTOR and Wnt (which, by the way, are strongly linked to cancer and other diseases) that can in some cases be (potentially) “druggable” or amenable to other future therapies.  These findings have potential implications for civilians as well.  Abstract:

According to a recent report from the Office of Suicide Prevention in the US Department of Veterans Affairs, veterans represent 8.5% of the US population, but account for 18% of all deaths from suicide. The aim of this study of psychiatric patients (n=39; 87% male) was to compare blood gene expression data from veterans with a history of one or more suicide attempts to veterans who had never attempted suicide. The attempter and non-attempter groups were matched for age and race/ethnicity, and both groups included veterans with a diverse psychiatric history that included posttraumatic stress disorder (PTSD) and substance-use disorders. Veterans were interviewed for lifetime psychiatric history, including a detailed assessment of prior suicide attempts and provided a blood sample. Results of Ingenuity Pathway Analysis (IPA) identified several pathways associated with suicide attempts, including the mammalian target of rapamycin (mTOR) and WNT signaling pathways. These pathways are of particular interest, given their role in explaining pharmacological treatments for suicidal behavior, including the use of ketamine and lithium. These results suggest that findings observed in civilians are also relevant for veterans and provide a context for interpreting results observed in post-mortem samples. In conclusion, an emerging body of work that shows consistency in findings across blood and brain samples suggests that it might be possible to identify molecular predictors of suicide attempts.

Nivolumab Vs. Ipilimumab For Melanoma

Nivolumab and ipilimumab are monoclonal antibodies useful in the treatment of advanced melanoma; these target "immune checkpoints" - the activity that suppresses immune system recognition of cancer.  Thus, these antibodies inhibit the checkpoints and allow the patient's immune system to better fight the cancer.  It seems that nivolumab is superior to ipilimumab in at least this study. Abstract:

Background Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. Methods In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. Results At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. Conclusions Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

Why not combine them?  Someone has thought of that, and it works well.

More on checkpoints here.

Strength Training Improves Cognitive Performance In Elderly Women

By Jonik - Own work, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=528985

Strength training in elderly women can not only enhance strength (and, hence, bodily function) but also increases “cognitive capabilities” (brain function).  This emphasizes brain-body connections and the utility of physical activity in maintaining mental as well as physical fitness.  Of course, given the possibility of injury or other negative effects, particularly in the elderly, interested individuals would need to consult their physician for the go-ahead, and get at least some sort of instruction in technique from a trainer or therapist.  Abstract:

Aging is a degenerative process marked by recognized functional, physiological, and metabolic impairments, such as dynapenia and diminished cognitive capacity. Therefore, the search for innovative strategies to prevent/delay these physiological and cognitive disorders is essential to guarantee the independence and life quality of an elderly population. The aim of this work is to verify the effect of a 12-week resistance exercise program on the general physical aptitude and cognitive capacities of elderly and sedentary women. Twenty-nine women (65.87±5.69 years) were divided into two groups. The control group was composed of eight elderly women who met the same inclusion criteria of the study and the strength training group was composed of 29 elderly women who were subjected to a resistance exercise program defined by 12 upper and lower limb exercises combined in 3×10 repetitions with 1-minute interval between repetitions and two resting minutes between exercises (three times/week). Weight loads were fixed between 60% and 75% of the apparent 1 repetition maximum, which was estimated by the test of 10 maximum repetitions. The direct curl was performed for upper body strength evaluation with 2.3 kg dumbbells for 30 seconds, whereas the chair test was used for lower body evaluation (total sit-stand movements in 30 seconds). The cognitive capacities of subjects were evaluated by "The Montreal Cognitive Assessment" questionnaire. After 12 weeks, the elderly group showed significant increases in the average upper body strength (58%), lower body strength (68%), and cognitive capacity (19%). The present study demonstrated that regular resistance exercises could provide significant gains on the upper and lower body strength concomitant to positive improvements on cognitive capacities of elderly women, bringing enhanced life quality.

Breakfast And Adolescent Girls

The study linked here suggests that eating breakfast doesn’t really help with respect to energy balance and physical activity during the day; however, it is restricted to adolescent girls and, also, apparently doesn’t look at how eating breakfast may affect school performance (should one take an exam on an empty stomach?).  So take it for what it is worth, an interesting data point, but limited   Abstract:

It is not known if breakfast consumption is an effective intervention for altering daily energy balance in adolescents when compared with breakfast omission. This study examined the acute effect of breakfast consumption and omission on free-living energy intake (EI) and physical activity (PA) in adolescent girls. Using an acute randomised cross-over design, forty girls (age 13·3 (sd 0·8) years, BMI 21·5 (sd 5·0) kg/m2) completed two, 3-d conditions in a randomised, counter-balanced order: no breakfast (NB) and standardised (approximately 1962 kJ) breakfast (SB). Dietary intakes were assessed using food diaries combined with digital photographic records and PA was measured via accelerometry throughout each condition. Statistical analyses were completed using repeated-measures ANOVA. Post-breakfast EI was 483 (sd 1309) kJ/d higher in NB v. SB (P=0·025), but total daily EI was 1479 (sd 11311) kJ/d higher in SB v. NB (P<0·0005). Daily carbohydrate, fibre and protein intakes were higher in SB v. NB (P<0·0005), whereas daily fat intake was not different (P=0·405). Effect sizes met the minimum important difference of ≥0·20 for all significant effects. Breakfast manipulation did not affect post-breakfast macronutrient intakes (P≥0·451) or time spent sedentary or in PA (P≥0·657). In this sample of adolescent girls, breakfast omission increased post-breakfast free-living EI, but total daily EI was greater when a SB was consumed. We found no evidence that breakfast consumption induces compensatory changes in PA. Further experimental research is required to determine the effects of extended periods of breakfast manipulation in young people.

Facial anti-inflammatory mask

Hello dear readers, 

This recipe for an anti-inflammatory mask has way too many ingredients; however, I do not want to subtract any of them since they all have proven inflammation-quenching qualities. 

If you a missing an ingredient or two, you can still go ahead and try it.

Here it is:
1 tsp of plain yogurt (any type, any fat content)
1/2 tsp raw honey
1 tsp or less of apple cider vinegar (with the mother)
3 drops of tea tree oil
3 crushed aspirin pills (uncoated)
a pinch of turmeric powder

Mix all in a plastic cup. Be careful to apply only on your face (turmeric stains everything). I keep the mask on my face until the mixture dries out and tightens the skin. Wash with water. If you are afraid that your skin will acquire yellow glow from the turmeric powder, then shorten the treatment. 

I routinely leave the mask for an hour on my face and if there is any residual color, I wipe off the skin with my recipe cleanser.