Early versus Delayed Tumor-Specific Therapy and Survival in Patients with Lung Cancer: A Retrospective Study.

INTRODUCTION: The timing of tumor-specific palliative therapy and its influence on the survival of patients with stage IV lung cancer remain unclear. METHODS: 375 patients with stage IV lung cancer who experienced an early or delayed therapy (early or delayed therapy group [TG]) were investigated using histology and ECOG performance score (ECOG-PS)-related subgroups. Kaplan-Meier and Cox regression analyses were used for survival analyses. RESULTS: Patients in the early TG had a significantly shorter median overall survival (OS) than those in the delayed TG (6 vs. 11 months). Patients with an ECOG-PS of ≥1 were significantly more present in the early TG than in the delayed TG (66.8 vs. 51.9%). But an early therapy was also significantly associated to a shorter median OS in ECOG-matched subgroups (ECOG-PS of 0, 7 vs. 23 months; ECOG ≥1, 6 vs. 8 months). An early therapy was associated to a significantly worse median OS in histological subgroups (NSCLC, 5 vs. 11 months; SCLC, 7 vs. 11 months) and was an independent risk factor in uni- and multivariate analyses. CONCLUSIONS: An early initiation of cancer-specific therapy was associated with a shorter survival time in palliative lung cancer patients, independent of the ECOG-PS and histological subtype.

Cancer therapy and treatments during COVID-19 era.

The COVID-19 pandemic has put a serious strain on health treatments as well at the economies of many nations. Unfortunately, there is not currently available vaccine for SARS-Cov-2/COVID-19. Various types of patients have delayed treatment or even routine check-ups and we are adapting to a virtual world. In many cases, surgeries are delayed unless they are essential. This is also true with regards to cancer treatments and screening. Interestingly, some existing drugs and nutraceuticals have been screened for their effects on COVID-19. Certain FDA approved drugs, vitamin, natural products and trace minerals may be repurposed to treat or improve the prevention of COVID-19 infections and disease progression. This review article will summarize how the treatments of various cancer patients has changed during the COVID-19 era as well as discuss the promise of some existing drugs and other agents to be repurposed to treat this disease.

[ELITE study - Nutrition, lifestyle and individual information for the prevention of stroke, dementia and heart attack - Study design and cardiovascular status]. / ELITE-Studie ­ Ernährung, Lebensstil und individuelle Information zur Verhinderung von Schlaganfall, Demenz und Herzinfarkt ­ Studiendesign und kardiovaskuläre Aufnahmedate.

BACKGROUND: For the prevention of cardiovascular risk factors (RF) there are numerous recommendations of professional societies, which relate to the personal way of life of individuals (for example nutrition/diet, physical activity, stress reduction etc.). The implementation of these recommendations is so far poor. In the ELITE study, data on RF, nutritional behavior, physical activity and quality of life in the Oldenburger Münsterland region are to be collected prospectively and improved by individual information. Reasons for the lack of implementation of preventive measures should be recognized. METHODS: The study is conducted as an interventional cohort study (DRKS-No.: 00 006 813, Ethics vote University of Göttingen). Up to 5000 people (with or without pre-existing RF) are aimed to be included. All participants receive a computer-generated report of their personal risk profile with detailed recommendations based on current guidelines. In addition, it is recommended to visit the family doctor to discuss the findings and, if necessary, initiate diagnostic or therapeutic measures. Every year, follow-up examinations take place for up to 5 years. RESULTS: By 31.12.2017 4602 participants (mean age 51.5 (±â€Š15.7) years, 53.7 % female) were admitted. Overweight were 39 % of the participants, obese 20.4 %. Most frequent anamnestic RF is hypertension (31.4 %), mean blood pressure was 138.4 ±â€Š16.6/83.0 ±â€Š9.9 mmHg. 2165 (47.0 %) participants show hypertensive blood pressure values. The second most frequent anamnestic RF are lipid metabolism disorders (16.6 %). CONCLUSION: The incidence of participants with at least one cardiovascular RF is very high (49.5 %, 16.6 % multiple RF). The incidence of RF is similar to other epidemiological data in Germany, so the ELITE collective allows a good comparison with other surveys.

Primary osteomyelofibrosis and an XX-male genotype.

A 62-yr-old man with two healthy daughters was diagnosed with osteomyelofibrosis. To our surprise, a female XX-karyotype was observed in bone marrow and confirmed in PHA-stimulated T-lymphocytes from peripheral blood. Further molecular genetic investigation revealed a submicroscopic translocation between the short arm of X and Y, which leads to an XX-male genotype based on an unbalanced translocation X;Y. This rare coincidence was further accentuated as the USP9Y gene, suspected to be to be involved in sperm cell production, was absent, but no azoospermia was present. In general, routine cytogenetics may result in findings that need to be further delineated and, as here, lead to a rare observation.

GSK-3 as potential target for therapeutic intervention in cancer.

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance.

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.

Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response.

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.

Targeting the cancer initiating cell: the ultimate target for cancer therapy.

An area of therapeutic interest in cancer biology and treatment is targeting the cancer stem cell, more appropriately referred to as the cancer initiating cell (CIC). CICs comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts in genetically modified murine models. CICs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation and metastasis. CICs may lay dormant after various cancer therapies which eliminate the more rapidly proliferating bulk cancer (BC) mass. However, CICs may remerge after therapy is discontinued as they may represent cells which were either intrinsically resistant to the original therapeutic approach or they have acquired mutations which confer resistance to the primary therapy. In experimental mouse tumor transplant models, CICs have the ability to transfer the tumor to immunocompromised mice very efficiently while the BCs are not able to do so as effectively. Often CICs display increased expression of proteins involved in drug resistance and hence they are intrinsically resistant to many chemotherapeutic approaches. Furthermore, the CICs may be in a suspended state of proliferation and not sensitive to common chemotherapeutic and radiological approaches often employed to eliminate the rapidly proliferating BCs. Promising therapeutic approaches include the targeting of certain signal transduction pathways (e.g., RAC, WNT, PI3K, PML) with small molecule inhibitors or targeting specific cell-surface molecules (e.g., CD44), with effective cytotoxic antibodies. The existence of CICs could explain the high frequency of relapse and resistance to many currently used cancer therapies. New approaches should be developed to effectively target the CIC which could vastly improve cancer therapies and outcomes. This review will discuss recent concepts of targeting CICs in certain leukemia models.

Glycobiology in malignant gliomas: expression and functions of galectins and possible therapeutic options.

Malignant gliomas, the most common malignant primary brain tumors, have a deleterious clinical prognosis of approximately 12 months in unselected series. The resistance against antineoplastic therapy is apparently not only associated with a high proliferative potential, marked antiapoptotic resistance and high migratory capacity. Effective mechanisms to escape the immune response of the organism and an intense neoangiogenesis also contribute to the aggressive growth of these neoplasms. In addition to a number of molecular mechanisms, the group of glycohydrate-binding galectins seems to contribute to the aggressive growth of malignant gliomas. Galectin-1, -3, -4 and -8 have been shown to be overexpressed in malignant gliomas. Galectin-1 is known to be involved in glioma cell migration and possibly also in proliferation. In this review, various aspects of glioma biology and their therapeutic relevance is discussed. The role of galectins in apoptosis-resistance, immune response and angiogenesis is discussed and explained why these molecules are interesting targets of glioma therapy.

Advances in targeting signal transduction pathways.

Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies.

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health.

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging.

Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health.

Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways.

Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for therapy. Recently the possibilities of more specific, targeted therapies have sparked the interest of clinical and basic researchers as approaches to kill cancer cells. However, there are also problems associated with these targeted therapies. Two key signaling pathways involved in the regulation of cell growth are the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Dysregulated signaling through these pathways is often the result of genetic alterations in critical components in these pathways as well as mutations in upstream growth factor receptors. Furthermore, these pathways may be activated by chemotherapeutic drugs and ionizing radiation. This review documents how their abnormal expression can contribute to drug resistance as well as resistance to targeted therapy. This review will discuss in detail PTEN regulation as this is a critical tumor suppressor gene frequently dysregulated in human cancer which contributes to therapy resistance. Controlling the expression of these pathways could improve cancer therapy and ameliorate human health.

Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy.

The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit "oncogene-addicted" growth, while they do display "cytokine-addicted" proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 hrs. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G(1) block, while paclitaxel triggered a G(2)/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not "oncogene-addicted" may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors.

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy.

The effects of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways on proliferation, drug resistance, prevention of apoptosis and sensitivity to signal transduction inhibitors were examined in FL/DeltaAkt-1:ER*(Myr(+)) + DeltaRaf-1:AR cells which are conditionally-transformed to grow in response to Raf and Akt activation. Drug resistant cells were isolated from FL/DeltaAkt-1:ER*(Myr(+)) + DeltaRaf-1:AR cells in the presence of doxorubicin. Activation of Raf-1, in the drug resistant FL/DeltaAkt-1:ER*(Myr(+)) + DeltaRaf-1:AR cells, increased the IC(50) for doxorubicin 80-fold, whereas activation of Akt-1, by itself, had no effect on the doxorubicin IC50. However, Akt-1 activation enhanced cell proliferation and clonogenicity in the presence of chemotherapeutic drugs. Thus the Raf/MEK/ERK pathway had profound effects on the sensitivity to chemotherapeutic drugs, and Akt-1 activation was required for the long term growth of these cells as well as resistance to chemotherapeutic drugs. The effects of doxorubicin on the induction of apoptosis in the drug resistant cells were enhanced by addition of either mTOR and MEK inhibitors. These results indicate that targeting the Raf/MEK/ERK and PI3K/Akt/mTOR pathways may be an effective approach for therapeutic intervention in drug resistant cancers that have mutations activating these cascades.

Dominant roles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs.

The effects of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways on cell cycle progression, gene expression, prevention of apoptosis and sensitivity to chemotherapeutic drugs were examined in FL/ΔAkt-1:ER*(Myr(+)) + ΔRaf-1:AR cells which are conditionally-transformed to grow in response to Raf-1 and Akt-1 activation by treatment with testosterone or tamoxifen respectively. In these cells we can compare the effects of normal cytokine vs. oncogene mediated signaling in the same cells by changing the culture conditions. Raf-1 was more effective than Akt-1 in inducing cell cycle progression and preventing apoptosis in the presence and absence of chemotherapeutic drugs. The normal cytokine for these cells, interleukin-3 induced/activated most downstream genes transiently, with the exception of p70S6K that was induced for prolonged periods of time. In contrast, most of the downstream genes induced by either the activate Raf-1 or Akt-1 oncogenes were induced for prolonged periods of time, documenting the differences between cytokine and oncogene mediated gene induction which has important therapeutic consequences. The FL/ΔAkt-1:ER*(Myr(+)) + ΔRaf-1:AR cells were sensitive to MEK and PI3K/mTOR inhibitors. Combining MEK and PI3K/mTOR inhibitors increased the induction of apoptosis. The effects of doxorubicin on the induction of apoptosis could be enhanced with MEK, PI3K and mTOR inhibitors. Targeting the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways may be an effective approach for therapeutic intervention in those cancers which have upstream mutations which result in activation of these pathways.