Targeting therapy-induced senescence as a novel strategy to combat chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting adverse effect of anticancer therapy that complicates the lifestyle of many cancer survivors. There is currently no gold-standard for the assessment or management of CIPN. Subsequently, understanding the underlying mechanisms that lead to the development of CIPN is essential for finding better pharmacological therapy. Therapy-induced senescence (TIS) is a form of senescence that is triggered in malignant and non-malignant cells in response to the exposure to chemotherapy. Recent evidence has also suggested that TIS develops in the dorsal root ganglia of rodent models of CIPN. Interestingly, several components of the senescent phenotype are commensurate with the currently established primary processes implicated in the pathogenesis of CIPN including mitochondrial dysfunction, oxidative stress, and neuroinflammation. In this article, we review the literature that supports the hypothesis that TIS could serve as a holistic mechanism leading to CIPN, and we propose the potential for investigating senotherapeutics as means to mitigate CIPN in cancer survivors.

Targeting tumor cell senescence and polyploidy as potential therapeutic strategies.

Senescence is a unique state of growth arrest that develops in response to a plethora of cellular stresses, including replicative exhaustion, oxidative injury, and genotoxic insults. Senescence has been implicated in the pathogenesis of multiple aging-related pathologies, including cancer. In cancer, senescence plays a dual role, initially acting as a barrier against tumor progression by enforcing a durable growth arrest in premalignant cells, but potentially promoting malignant transformation in neighboring cells through the secretion of pro-tumorigenic drivers. Moreover, senescence is induced in tumor cells upon exposure to a wide variety of conventional and targeted anticancer drugs (termed Therapy-Induced Senescence-TIS), representing a critical contributing factor to therapeutic outcomes. As with replicative or oxidative senescence, TIS manifests as a complex phenotype of macromolecular damage, energetic dysregulation, and altered gene expression. Senescent cells are also frequently polyploid. In vitro studies have suggested that polyploidy may confer upon senescent tumor cells the ability to escape from growth arrest, thereby providing an additional avenue whereby tumor cells escape the lethality of anticancer treatment. Polyploidy in tumor cells is also associated with persistent energy production, chromatin remodeling, self-renewal, stemness and drug resistance - features that are also associated with escape from senescence and conversion to a more malignant phenotype. However, senescent cells are highly heterogenous and can present with variable phenotypes, where polyploidy is one component of a complex reversion process. Lastly, emerging efforts to pharmacologically target polyploid tumor cells might pave the way towards the identification of novel targets for the elimination of senescent tumor cells by the incorporation of senolytic agents into cancer therapeutic strategies.

Therapy-induced senescence as a component of tumor biology: Evidence from clinical cancer.

Therapy-Induced Senescence (TIS) is an established response to anticancer therapy in a variety of cancer models. Ample evidence has characterized the triggers, hallmarks, and functional outcomes of TIS in preclinical studies; however, limited evidence delineates TIS in clinical cancer (human tumor samples). We examined the literature that investigated the induction of TIS in samples derived from human cancers and highlighted the major findings that suggested that TIS represents a main constituent of tumor biology. The most frequently utilized approach to identify TIS in human cancers was to investigate the protein expression of senescence-associated markers (such as cyclins, cyclin-dependent kinase inhibitors, Ki67, DNA damage repair response markers, DEC1, and DcR1) via immunohistochemical techniques using formalin-fixed paraffin-embedded (FFPE) tissue samples and/or testing the upregulation of Senescence-Associated ß-galactosidase (SA-ß-gal) in frozen sections of unfixed tumor samples. Collectively, and in studies where the extent of TIS was determined, TIS was detected in 31-66% of tumors exposed to various forms of chemotherapy. Moreover, TIS was not only limited to both malignant and non-malignant components of tumoral tissue but was also identified in samples of normal (non-transformed) tissue upon chemo- or radiotherapy exposure. Nevertheless, the available evidence continues to be limited and requires a more rigorous assessment of in vivo senescence based on novel approaches and more reliable molecular signatures. The accurate assessment of TIS will be beneficial for determining its relevant contribution to the overall outcome of cancer therapy and the potential translatability of senotherapeutics.

PD-L1 expression in breast invasive ductal carcinoma with incomplete pathological response to neoadjuvant chemotherapy.

OBJECTIVES: To investigate the expression of programmed death-ligand 1 (PD-L1) in breast cancer in association with incomplete pathological response (PR) to neoadjuvant chemotherapy (NAC). METHODS: PD-L1 expression was evaluated using immunohistochemistry in post-operative, post-NAC samples of 60 patients (n = 60) diagnosed with breast invasive ductal carcinoma with incomplete PR to NAC, including 31 matched pre-NAC and post-NAC samples (n = 31). PD-L1 protein expression was assessed using three scoring approaches, including the tumor proportion score (TPS), the immune cell score (ICS), and the combined tumor and immune cell score (combined positive score, CPS) with a 1% cut-off. RESULTS: In the post-operative, post-NAC samples (n = 60), positive expression rate of PD-L1 was observed in 18.3% (11/60) of cases by TPS, 31.7% (19/60) by ICS, and 25% (15/60) by CPS. In matched samples, positive expression rate of PD-L1 was observed in 19.3% (6/31) of patients by TPS, 51.6% (16/31) by ICS, and 19.3% (6/31) by CPS in pre-NAC specimens, while it was observed in 22.6% (7/31) of matched post-NAC samples by TPS, 22.6% (7/31) by ICS, and 19.3% (6/31) by CPS. In the matched samples, there was a significant decrease in PD-L1 immunoexpression using ICS in post-NAC specimens (McNemar's, p = 0.020), while no significant differences were found using TPS and CPS between pre- and post-NAC samples (p = 1.000, p = 0.617; respectively). PD-L1 immunoexpression determined by TPS or CPS was only significantly associated with ER status (p = 0.022, p = 0.021; respectively), but not with other clinicopathological variables. We could not establish a correlation between PD-L1 expression and the overall survival rate (p > 0.05). There were no significant differences in the tumor infiltrating lymphocytes count between the paired pre- and post-NAC samples (t = 0.581, p = 0.563 or Wilcoxon's Signed Rank test; z = -0.625, p = 0.529). CONCLUSION: Our findings indicate that PD-L1 protein expression in infiltrating immune cells was significantly reduced in breast tumors that developed incomplete PR following the exposure to NAC.

The Expression of the Senescence-Associated Biomarker Lamin B1 in Human Breast Cancer.

Senescence is a major response to cancer chemotherapy and has been linked to unfavorable therapy outcomes. Lamin B1 is a component of the nuclear lamina that plays a pivotal role in chromatin stability. Downregulation of lamin B1 represents an established biomarker for cellular senescence. However, the protein expression level of lamin B1 in malignant tissue, particularly of the breast, has not been previously described. In this work, we investigated lamin B1 protein expression in normal breast epithelium, malignant breast tissue (including adjacent non-malignant tissue) and in malignant tissue exposed to neoadjuvant chemotherapy (NAC) using immunohistochemistry (IHC) in three patient groups (n = 15, n = 87, and n = 43, respectively). Our results indicate that lamin B1 mean positive expression was 93% in normal breast epithelium and 88% in malignant breast cells, but significantly decreased (mean: 55%, p < 0.001) in malignant breast tissue after exposure to NAC, suggestive of senescence induction. No significant association between lamin B1 expression and other clinicopathological characteristics or survival of breast cancer patients was recorded. To our knowledge, this is the first report that established the baseline protein expression level of lamin B1 in normal and malignant breast tissue, and its reduction following exposure to chemotherapy. In conclusion, lamin B1 downregulation can be used reliably as a component of multiple biomarker batteries to identify therapy-induced senescence (TIS) in clinical cancer.

Paracetamol: unconventional uses of a well-known drug.

OBJECTIVES: To describe and map what is known about unconventional uses of paracetamol through a scoping review of published literature by adopting adopted a PRISMA systematic approach methodology. KEY FINDINGS: Four themes for unconventional uses of paracetamol emerged: (a) use of paracetamol in sleep (a-1) positive effect of paracetamol on sleep (n = 9) or (a-2) neutral or negative effect of paracetamol on sleep (n = 9); (b) use of paracetamol in sport (n = 13); (c) mixing paracetamol with drinks, waterpipe and illicit drugs (n = 5); and (d) miscellaneous uses (n = 4). Forty records were reviewed and charted. Available literature supports concern around the potential of harmful or non-medical use of paracetamol, especially among patients with a history of substance use, parents of young children or athletes. SUMMARY: Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It is considered remarkably safe if used within instructions. However, there is growing evidence that paracetamol, is sometimes used outside approved indications or abused (i.e. used for non-medical reasons). This review highlights the need for enhanced pharmacovigilance and surveillance of non-medical paracetamol use and raising general public awareness of its potential dangers especially in higher than recommended doses.

Autophagy and senescence in cancer therapy.

Tumor cells can undergo diverse responses to cancer therapy. While apoptosis represents the most desirable outcome, tumor cells can alternatively undergo autophagy and senescence. Both autophagy and senescence have the potential to make complex contributions to tumor cell survival via both cell autonomous and cell non-autonomous pathways. The induction of autophagy and senescence in tumor cells, preclinically and clinically, either individually or concomitantly, has generated interest in the utilization of autophagy modulating and senolytic therapies to target autophagy and senescence, respectively. This chapter summarizes the current evidence for the promotion of autophagy and senescence as fundamental responses to cancer therapy and discusses the complexity of their functional contributions to cell survival and disease outcomes. We also highlight current modalities designed to exploit autophagy and senescence in efforts to improve the efficacy of cancer therapy.

Medical students' relative immunity, or lack thereof, against COVID-19 emotional distress and psychological challenges; a descriptive study from Jordan.

Background: Emotional distress is a major impact of COVID-19 among not only the general public but also healthcare workers including medical students. This study aimed at describing self-reported changes in emotional reactions associated with COVID-19 among medical students in Jordan and to assessing the potential effect of social media utilization on emotional distress among this group. Methods: A cross-sectional design was utilized to collect data early on during the outbreak in Jordan. All medical students in Jordan were eligible to complete an online questionnaire assessing self-reported emotional reactions to COVID-19 that covered four main domains: negative emotion (anxiety, worry, depression, panic, loneliness, and nervousness), positive emotion (happiness, joy, and excitement), sleep disorders (insomnia, shallow sleep, nightmares, and insufficient sleep), and aggression (verbal argument and physical fighting). The frequency of social media utilization as a main source of COVID-19 information was also assessed. Results: 59.9% of participants were females, 64.9% were enrolled at the two major medical schools in Jordan, and 59.6% were in the pre-clinical stage (years). A significant proportion of participants self-reported increased negative emotional levels of anxiety (49.2%), worry (72.4%), depression (23.1%), panic (22.6%), and nervousness (38.2%) and decreased positive emotional levels of happiness (44.8%), joy (47.3%), and feelings of excitement (45.1%). Self-reported sleep disorders were not as common (less than 15% for any of the four items), while arguing with others was at 26.7%. Significant differences by gender and academic year were detected. Almost half of participants reported using social media as a main source of COVID-19 information "most/all-the-times" with a significant effect of such on reducing emotional distress. Conclusion: The results suggest a potential effect of COVID-19 on the emotional distress of medical students. Addressing and mitigating such effects is crucial. The potential buffering effect of social media should be further investigated.

Therapy-Induced Senescence: An "Old" Friend Becomes the Enemy.

For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

Medical Students and COVID-19: Knowledge, Attitudes, and Precautionary Measures. A Descriptive Study From Jordan.

The recent coronavirus disease (COVID-19) pandemic is associated with increasing morbidity and mortality and has impacted the lives of the global populations. Human behavior and knowledge assessment during the crisis are critical in the overall efforts to contain the outbreak. To assess knowledge, attitude, perceptions, and precautionary measures toward COVID-19 among a sample of medical students in Jordan. This is a cross-sectional descriptive study conducted between the 16th and 19th of March 2020. Participants were students enrolled in different levels of study at the six medical schools in Jordan. An online questionnaire which was posted on online platforms was used. The questionnaire consisted of four main sections: socio-demographics, sources of information, knowledge attitudes, and precautionary measures regarding COVID-19. Medical students used mostly social media (83.4%) and online search engines (84.8%) as their preferred source of information on COVID-19 and relied less on medical search engines (64.1%). Most students believed that hand shaking (93.7%), kissing (94.7%), exposure to contaminated surfaces (97.4%), and droplet inhalation (91.0%) are the primary mode of transmission but were indecisive regarding airborne transmission with only 41.8% in support. Participants also reported that elderly with chronic illnesses are the most susceptible group for the coronavirus infection (95.0%). As a response to the COVID-19 pandemic more than 80.0% of study participants adopted social isolation strategies, regular hand washing, and enhanced personal hygiene measures as their first line of defense against the virus. In conclusion, Jordanian medical students showed expected level of knowledge about the COVID-19 virus and implemented proper strategies to prevent its spread.