An Insight on Novel Molecular Pathways in Metastatic Prostate Cancer: A Focus on DDR, MSI and AKT

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment approaches. Genomic profiling has evidenced that DNA damage repair genes’ alterations are quite frequent in metastatic, castration resistant prostate cancer and specific therapies can interfere with this pathway, showing promising activity in this setting. Microsatellite instability is gaining attention as it seems to represent a predictive factor of the response to immunotherapy. Furthermore, the PTEN-PI3K-AKT pathway is another possible treatment target being investigated. In this review, we explore the current knowledge on these frequent genomic alterations of metastatic prostate cancer, their possible therapeutic repercussions and the promising future treatments under evaluation.

Endodontic retreatment: significance and a systematic review of te major protocols

Introduction: In the endodontic treatment scenario, despite the emergence of techniques and instruments that facilitate the treatment, there are still cases that require retreatment of the treated root canals. Non-surgical endodontic retreatment (NSER) can be performed in one or several visits. Endodontic pain has been the main reason for patient consultations after therapy and affects patient comfort. A condition for successful endodontic retreatment is proper cleaning of the root canals, therefore, special attention must be given to the technique used to remove the filling material, with the most commonly used cement, pastes, and gutta-percha cones. Objective: This systematic review aimed to evaluate the main protocols and techniques for endodontic retreatment. Methods: The present study was followed by a systematic literature review model. Clinical studies were included as case reports, retrospective, prospective and randomized trials with qualitative and/or quantitative analysis. The quality of the studies was based on the GRADE instrument. The risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: The results showed that cleaning and the presence of debris at a speed of 1500 rpm provided greater agility with a smaller number of fractured instruments. Furthermore, the dynamic navigation system enabled the minimally invasive removal of the fiber post with a high degree of precision, without unnecessary removal of the root structure. One visit NSER had lower postoperative pain than multiple visits only for 1 and 30 days. Ultrasonic tips should be considered a good option for endodontic retreatment, especially for cases of bioceramics. Finally, there is a predominance of E. faecalis and P. gingivalis in all phases of endodontic retreatment.

Stress responses as master keys to epigenomic changes in transcriptome and metabolome for cancer etiology and therapeutics

From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that facilitate survival and maintain their existence. Different kinds of stress stimuli trigger epigenetic alterations in cancer cells, which leads to changes in their transcriptome and metabolome, ultimately resulting in suppression of growth inhibition or induction of apoptosis. Whether cancer cells show a protective response to stress or succumb to cell death depends on the type of stress and duration of exposure. A thorough understanding of epigenetic and molecular architecture of cancer cell stress response pathways can unveil a plethora of information required to develop novel anti-cancer therapeutics. The present view highlights current knowledge about alterations in epigenome and transcriptome of cancer cells as a consequence of exposure to different physicochemical stressful stimuli such as reactive oxygen species (ROS), hypoxia, radiation, hyperthermia, genotoxic agents, and nutrient deprivation. Currently, an anti-cancer treatment scenario involving the imposition of stress on target cancer cells is gaining traction to augment or even replace conventional therapeutic regimens. Therefore, a comprehensive understanding of stress response pathways is crucial for devising and implementing novel therapeutic strategies.

Safety and Efficacy of Daclatasvir with Sofosbuvir and Ribavirin in Hepatitis C Virus Infection: A Real World Experience from South Punjab, Pakistan

Background & Objectives: Sofosbuvir (SOF) and daclatasvir (DCV) in combination with ribavirin (RBV) drastically changed the treatment scenario of chronic hepatitis C (CHC) patients, achieving remarkable efficacy and safety profile. Real world experience of SOF/DCV/RBV combination in this part of Asia was scant. This study aimed to evaluate the efficacy and safety of SOF/DCV/RBV combination to treat CHC patients at a tertiary care hospital in South Punjab. Methods: Patients of CHC of any genotype were enrolled prospectively. They were treated with 12 weeks course of SOF/DCV/RBV combination. Effectiveness was evaluated by end of treatment response (ETR) and sustained virological response (SVR) at 12 and 24 weeks post-treatment. Adverse events were recorded for safety analysis. Results: We analyzed data of 102 patients of CHC (40 males and 62 females). The mean age was 40.04 + 10.22 years. Mean weight was 67.24 + 11.78 kg, while mean body mass index (BMI) was 26.32 + 4.58 kg/m2. Eighty patients belonged to low socio-economic status, while 22 belonged to middle socio-economic status. Sixty-four had a rural background, while 38 were from urban background. Seventy-four patients had no co-morbid condition; 16 (15.7%) had diabetes and 12 (11.8%) patients had co-morbid hypertension. Ninety percent of the patients did not have cirrhosis; 6% had compensated liver disease, while 4 % had decompensated liver disease. All the patients achieved undetectable HCV RNA at the end of treatment and 12 weeks after completion of treatment, while SVR at 24 weeks was achieved in 98% of patients. Only 2 patients discontinued treatment as a result of side effects. The most common side effects reported include fatigue, headache and fever. Conclusion: CHC is a grave problem in developing countries like Pakistan. The SOF/DCV/RBV combination is very effective in eradicating CHC and has a very good side effect profile as well.

Soluble Biomarkers with Prognostic and Predictive Value in Advanced Non-Small Cell Lung Cancer Treated with Immunotherapy

Numerous targeted therapies have been evaluated for the treatment of non-small cell lung cancer (NSCLC). To date, however, only a few agents have shown promising results. Recent advances in cancer immunotherapy, most notably immune checkpoint inhibitors (ICI), have transformed the treatment scenario for these patients. Although some patients respond well to ICIs, many patients do not benefit from ICIs, leading to disease progression and/or immune-related adverse events. New biomarkers capable of reliably predicting response to ICIs are urgently needed to improve patient selection. Currently available biomarkers—including programmed death protein 1 (PD-1) and its ligand (PD-L1), and tumor mutational burden (TMB)—have major limitations. At present, no well-validated, reliable biomarkers are available. Ideally, these biomarkers would be obtained through less invasive methods such as plasma determination or liquid biopsy. In the present review, we describe recent advances in the development of novel soluble biomarkers (e.g., circulating immune cells, TMB, circulating tumor cells, circulating tumor DNA, soluble factor PD-L1, tumor necrosis factor, etc.) for patients with NSCLC treated with ICIs. We also describe the potential use of these biomarkers as prognostic indicators of treatment response and toxicity.

Chronic Kidney Disease: Current Scenario of diagnosis and treatment in India

Chronic Kidney Disease (CKD) is one of the most burdensome disease with high mortality rate globally. Even though there are diagnostically accepted markers for the detection of CKD, the unreliability of the non-specific marker is a lacuna in the clinical world for an early prognosis and prevention of this chronic disease. Further, the economically challenging conventional treatment options available currently are a burden for many low-income countries to overcome this disease. This article discusses the current treatment scenario for CKD, and limitations of the diagnostic and treatment options available for CKD.

Adjuvant Treatment in Pancreatic Cancer: Shaping the Future of the Curative Setting

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease even in the early stages, despite progresses in surgical and pharmacological treatment in recent years. High potential for metastases is the main cause of therapeutic failure in localized disease, highlighting the current limited knowledge of underlying pathological processes. However, nowadays research is focusing on the search for personalized approaches also in the adjuvant setting for PDAC, by implementing the use of biomarkers and investigating new therapeutic targets. In this context, the aim of this narrative review is to summarize the current treatment scenario and new potential therapeutic approaches in early stage PDAC, from both a preclinical and clinical point of view. Additionally, the review examines the role of target therapies in localized PDAC and the influence of neoadjuvant treatments on survival outcomes.

LMD-18. Detection and serial monitoring of CSF ctDNA in breast cancer leptomeningeal disease (BCLM)

Background CSF cytology is the gold standard diagnostic test for BCLM, but is hampered by a low sensitivity, often necessitating repeated lumbar puncture to confirm or refute the diagnosis. Furthermore, during the treatment of BCLM, there is no robust quantitative response tool to guide treatment decisions. Material and Methods cfDNA was obtained from CSF and plasma in patients with breast cancer undergoing investigation for BCLM (n = 28) and during subsequent intrathecal treatment (n = 13). Ultra low pass whole genome sequencing (ulpWGS) and estimation of the ctDNA fraction was performed. Results were validated by mutation-specific digital droplet PCR (ddPCR). Results 22/28 cases had confirmed BCLM by positive MRI and/or CSF cytology. The remaining 6/28 had suspected but non-confirmed BCLM, and at median 20 months follow up, these patients were BCLM-free. CSF ctDNA fraction was significantly elevated (median 57.5, IQR 38.3 - 84.9%) in confirmed BCLM compared to 6 non-confirmed BCLM (median 5.0, IQR 0.0 - 6.7%) (p <0.0001). ctDNA fraction was detected in BCLM confirmed cases regardless of negative cytology or MRI. Plasma ctDNA fraction was only detected in extra-cranial disease progression. ctDNA fraction was concordant with mutant allele fraction measured by ddPCR (n = 118 samples). Serial CSF ctDNA fraction during intrathecal treatment showed dynamic changes, while CSF cytology and MRI were often unchanged or equivocal. Early reduction in CSF ctDNA fraction was associated with longer responses to intrathecal therapy. Further, rising ctDNA fraction during intrathecal chemotherapy could be detected up to 6 weeks before relapse in neurological symptoms, cytology or MRI. Conclusion Measuring CSF ctDNA fraction is a sensitive diagnostic test for BCLM and could lead to more timely and accurate diagnosis. During intrathecal chemotherapy, CSF ctDNA also provides a quantitative response biomarker to help guide clinical management in this difficult treatment scenario.

New Perspectives on Green Energy Defaults

This paper is an attempt to provide new perspectives on green energy defaults (GED) that promote the purchase of renewable energy electricity (REe) among consumers. We aim to complement existing studies and improve the understanding of GED, particularly when they are less, or unexpectedly, effective. To that end, we run a randomized controlled experiment and take the UK as a case study. We replicate the research design of previous lab experiments for comparative reasons. We also expand the analytical framework, identify key determinants and compare stated versus revealed preferences. Initial results indicate a lack of effectiveness across all treatment groups. This seems to challenge most of the existing lab experimental evidence and questions external validity claims. In addition to the actual treatments, current tariff agreements appear as significant determinants of choices. Nevertheless, when stated and revealed preferences are analysed, statistical tests revealed positive and significant differential effects, suggesting that the sole provision of an explicit, simple decision framework can trigger a greater adoption of REe, even in an opt-in treatment scenario. We thus argue that GED can still influence consumer decision-making in the desired policy direction. However, outcomes are likely to be context-specific so policy generalisations are not advisable. Building upon existing knowledge and our experimental results, we propose various motivational and contextual issues affecting consumer behaviour and thus the effectiveness and suitability of GED. They can offer guidance for future GED studies, particularly in countries in which market and consumer policy conditions for REe may be less advanced or certain.

Role of 4-Thiazolidinone Scaffold in Targeting Variable Biomarkers and Pathways Involving Cancer

Background: Cancer can be considered as a genetic as well as a metabolic disorder. Current cancer treatment scenario looks like aggravating tumor cell metabolism, causing the disease to progress even with greater intensity. The cancer therapy is restricted to limitations of poor patient compliance due to toxicities to normal tissues and multi-drug resistance development. There is an emerging need for cancer therapy to be more focused on the better understanding of genetic, epigenetic and transcriptional changes resulting in cancer progression and their relationship with treatment sensitivity. Objective: The 4-thiazolidinone nucleus possesses marked anticancer potential towards different biotargets, thus targeting different cancer types like breast, prostate, lung, colorectal and colon cancers, renal cell adenocarcinomas and gliomas. Therefore, conjugating the 4-thiazolidinone scaffold with other promising moieties or by directing the therapy towards targeted drug delivery systems like the use of nanocarrier systems, can provide the gateway for optimizing the anticancer efficiency and minimizing the adverse effects and drug resistance development, thus providing stimulus for personalized pharmacotherapy. Methods: An exhaustive literature survey has been carried out to give an insight into the anticancer potential of the 4-thiazolidinone nucleus either alone or in conjugation with other active moieties, with the mechanisms involved in preventing proliferation and metastasis of cancer covering a vast range of publications of repute. Conclusion: This review aims to summarise the work reported on anticancer activity of 4-thiazolidinone derivatives covering various cancer biomarkers and pathways involved, citing the data from 2005 till now, which may be beneficial to the researchers for future development of more efficient 4-thiazolidinone derivatives.