Concurrent hypoxia and apoptosis imparts immune programming potential in mesenchymal stem cells: Lesson from acute graft-versus-host-disease model.

BACKGROUND: Mesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy. METHODS: Human MSCs were derived from bone marrow (BM) and Wharton's Jelly (WJ) and preconditioned through exposure to hypoxia and induction of apoptosis, either sequentially or simultaneously. The immune programming potential of preconditioned MSCs was evaluated by assessing their effects on T cell proliferation, induction of Tregs, programming of effector T-cell towards Th2 phenotype, macrophage polarization in the direct co-culture of MSCs and aGVHD patients-derived PBMNCs. Additionally, efferocytosis of MSCs and relative change in the expression of immunomodulatory soluble factors were examined. RESULTS: Our study demonstrated that hypoxia preconditioned apoptotic MSCs (BM-MSCs, WJ-MSCs) bear more immune programming ability in a cellular model of acute Graft-versus-Host-Disease (aGVHD). Our findings revealed that WJ-MSCsHYP+APO were superior to BM-MSCsHYP+APO for immune regulation. These induced the differentiation of CD4+T-cell into Tregs, enhanced Th2 effector responses, and simultaneously mitigated Th1- and Th17 responses. Additionally, this approach led to the polarization of M1 macrophages toward an M2 phenotype. CONCLUSION: Our study highlights the potential of WJ-MSCs conditioned with hypoxia and apoptosis concurrently, as a promising therapeutic strategy for aGVHD. It underscores the importance of considering MSC apoptosis in optimizing MSCs-based cellular therapy protocols for enhanced therapeutic efficacy in aGvHD.

Belling the "cat": Wnt/ß-catenin signaling and its significance in future cancer therapies.

The WNT/ß-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/ß-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT 'On' or 'Off' mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/ß-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/ß-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/ß-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/ß-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/ß-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/ß-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/ß-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/ß-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/ß-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.

CAR T-cell therapy in cancer: Integrating nursing perspectives for enhanced patient care.

Chimeric antigen receptor (CAR) T-cell therapy represents a significant advancement in cancer treatment, particularly for hematologic malignancies. Various cancer immunotherapy strategies are presently being explored, including cytokines, cancer vaccines, immune checkpoint inhibitors, immunomodulators monoclonal antibodies, etc. The therapy has shown impressive efficacy in treating conditions such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma, often leading to complete remission in refractory cases. However, the clinical application of CAR T-cell therapy is accompanied by challenges, notably severe side effects. Effective management of these adverse effects requires meticulous monitoring and prompt intervention, highlighting the critical role of nursing in this therapeutic process. Nurses play a crucial role in patient education, monitoring, symptom management, care coordination, and psychosocial support, ensuring safe and effective treatment. As research advances and new CAR T-cell therapies are developed, the role of nursing professionals remains pivotal in optimizing patient outcomes. The continued evolution of CAR T-cell therapy promises improved outcomes, with nursing professionals integral to its success.

Canonical WNT/ß-catenin signaling upregulates aerobic glycolysis in diverse cancer types.

Despite many efforts, a comprehensive understanding and clarification of the intricate connections within cancer cell metabolism remain elusive. This might pertain to intracellular dynamics and the complex interplay between cancer cells, and cells with the tumor stroma. Almost a century ago, Otto Warburg found that cancer cells exhibit a glycolytic phenotype, which continues to be a subject of thorough investigation. Past and ongoing investigations have demonstrated intricate mechanisms by which tumors modulate their functionality by utilizing extracellular glucose as a substrate, thereby sustaining the essential proliferation of cancer cells. This concept of "aerobic glycolysis," where cancer cells (even in the presence of enough oxygen) metabolize glucose to produce lactate plays a critical role in cancer progression and is regulated by various signaling pathways. Recent research has revealed that the canonical wingless-related integrated site (WNT) pathway promotes aerobic glycolysis, directly and indirectly, thereby influencing cancer development and progression. The present review seeks to gather knowledge about how the WNT/ß-catenin pathway influences aerobic glycolysis, referring to relevant studies in different types of cancer. Furthermore, we propose the concept of impeding the glycolytic phenotype of tumors by employing specific inhibitors that target WNT/ß-catenin signaling.

The future of cancer treatment: combining radiotherapy with immunotherapy.

Radiotherapy (RT) and immunotherapy (IT) are the powerful tools for cancer treatment which act through the stimulation of immune response, and evidence suggest that combinatorial actions of these therapies may augment each other's beneficial effect through complex synergistic mechanisms. These molecular strategies are designed to target rapidly dividing cancer cells by either directly or indirectly inducing DNA damage. However, when cells detect DNA damage, they activate a range of signalling pathways known as the DNA damage response (DDR) to repair. Strategies are being developed to interfere with the DDR pathways in cancer cells to ensure their damage-induced degeneration. The stability of a cell's genetic material is largely dependent on the efficacy of DNA repair and therefore, an in-depth understanding of DNA damages and repair mechanism(s) in cancer cells is important to develop a promising therapeutic strategies for ensuring the efficacy of damage-induced tumor cell death. In recent years, a wide range of small molecule drugs have been developed which are currently being employed to combat the DNA repair deficiencies associated with tumor cells. Sequential or concurrent use of these two modalities significantly enhances the anti-tumor response, however with a concurrent probability of increased incidence of symptomatic adverse effects. With advent of newer IT agents, and administration of higher doses of radiation per fraction, such effects are more difficult to predict owing to the paucity of randomized trial data. It is well established that anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti- Programmed cell death protein 1(PD-1), anti-Programmed cell death one ligand 1 (PD-L1) can be safely administered with RT and many studies have demonstrated survival benefit with such combination for patients with metastatic malignancy. However, the biology of radioimmunotherapy (RT/IT) is still an open area where research need to be focused to determine optimum dosage specially the interaction of the RT/IT pathways to determine optimum dosing schedule. In the current article we have summarised the possible intracellular immunological events that might be triggered when RT and IT modalities are combined with the DDR antagonists and highlighted present clinical practices, outcome, and toxicity profile of this novel treatment strategy.

7-amino carboxycoumarin 2 inhibits lactate induced epithelial-to-mesenchymal transition via MPC1 in oral and breast cancer cells.

Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta-analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA-MB-231) with sodium L-lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L-lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.

Unveiling HPV's hidden link: Cardiovascular diseases and the viral intrigue.

Cardiovascular diseases (CVD) remain a major global health challenge, with an escalating impact on mortality despite advancements in managing conventional risk factors. This review investigates the intricate relationship between human papillomavirus (HPV) and CVD, shedding light on a novel aspect of cardiovascular health. Despite significant progress in understanding and managing traditional CVD risk factors, a substantial proportion of CVD cases lack these conventional markers. Recent research has unveiled HPV, a prevalent sexually transmitted infection, as a potential unconventional risk factor for CVD. This review delves into the underlying mechanisms linking HPV to CVD pathogenesis. HPV's influence on vascular endothelium and induction of systemic inflammation are key contributors. Additionally, HPV disrupts host lipid metabolism, further exacerbating the development of atherosclerosis. The link between HPV and CAD is not merely correlative; it encompasses a complex interplay of virological, immunological, and metabolic factors. Understanding the connection between HPV and CVD holds transformative potential. Insights from this review not only underscore the significance of considering HPV as a crucial risk factor but also advocate for targeted HPV screening and vaccination strategies to mitigate CVD risks. This multidisciplinary exploration bridges the gap between infectious diseases and cardiovascular health, emphasizing the need for a comprehensive approach to combating the global burden of cardiovascular disease. Further research and clinical guidelines in this realm are essential to harness the full scope of preventive and therapeutic interventions, ultimately shaping a healthier cardiovascular landscape.

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. METHODS: In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. RESULTS: In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). CONCLUSION: Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond.

Significant progress has been achieved in the realm of therapeutic interventions for multiple myeloma (MM), leading to transformative shifts in its clinical management. While conventional modalities such as surgery, radiotherapy, and chemotherapy have improved the clinical outcomes, the overarching challenge of effecting a comprehensive cure for patients afflicted with relapsed and refractory MM (RRMM) endures. Notably, adoptive cellular therapy, especially chimeric antigen receptor T-cell (CAR-T) therapy, has exhibited efficacy in patients with refractory or resistant B-cell malignancies and is now also being tested in patients with MM. Within this context, the B-cell maturation antigen (BCMA) has emerged as a promising candidate for CAR-T-cell antigen targeting in MM. Alternative targets include SLAMF7, CD38, CD19, the signaling lymphocyte activation molecule CS1, NKG2D, and CD138. Numerous clinical studies have demonstrated the clinical efficacy of these CAR-T-cell therapies, although longitudinal follow-up reveals some degree of antigenic escape. The widespread implementation of CAR-T-cell therapy is encumbered by several barriers, including antigenic evasion, uneven intratumoral infiltration in solid cancers, cytokine release syndrome, neurotoxicity, logistical implementation, and financial burden. This article provides an overview of CAR-T-cell therapy in MM and the utilization of BCMA as the target antigen, as well as an overview of other potential target moieties.

ß-catenin inhibitors in cancer therapeutics: intricacies and way forward.

ß-catenin is an evolutionary conserved, quintessential, multifaceted protein that plays vital roles in cellular homeostasis, embryonic development, organogenesis, stem cell maintenance, cell proliferation, migration, differentiation, apoptosis, and pathogenesis of various human diseases including cancer. ß-catenin manifests both signaling and adhesive features. It acts as a pivotal player in intracellular signaling as a component of versatile WNT signaling cascade involved in embryonic development, homeostasis as well as in carcinogenesis. It is also involved in Ca2+ dependent cell adhesion via interaction with E-cadherin at the adherens junctions. Aberrant ß-catenin expression and its nuclear accumulation promote the transcription of various oncogenes including c-Myc and cyclinD1, thereby contributing to tumor initiation, development, and progression. ß-catenin's expression is closely regulated at various levels including its stability, sub-cellular localization, as well as transcriptional activity. Understanding the molecular mechanisms of regulation of ß-catenin and its atypical expression will provide researchers not only the novel insights into the pathogenesis and progression of cancer but also will help in deciphering new therapeutic avenues. In the present review, we have summarized the dual functions of ß-catenin, its role in signaling, associated mutations as well as its role in carcinogenesis and tumor progression of various cancers. Additionally, we have discussed the challenges associated with targeting ß-catenin molecule with the presently available drugs and suggested the possible way forward in designing new therapeutic alternatives against this oncogene.

Passage number of cancer cell lines: Importance, intricacies, and way-forward.

Cancer cell lines play a crucial role as invaluable models in cancer research, facilitating the examination of cancer progression as well as the advancement of diagnostics and treatments. While they may not perfectly replicate the original tumor, they generally exhibit similar characteristics. Low-passage cancer cell lines are generally preferred due to their closer resemblance to the original tumor, as long-term culturing can alter the genetic and molecular profiles of a cell line thereby highlighting the importance of monitoring the passage number (PN). Variations in proliferation, migration, gene expression, and drug sensitivity can be linked to PN differences. PN can also influence DNA methylation levels, metabolic profiles, and the expression of genes/or proteins in cancer cell lines. When conducting research on cancer cell lines, it is crucial for researchers to carefully select the appropriate PN to maintain consistency and reliability of results. Moreover, to ensure dependability and replicability, scientists ought to actively track the growth, migration, and gene/or protein profiles of cancer cell lines at specific PNs. This approach enables the identification of the most suitable range of PNs for experiments, guaranteeing consistent and precise results. Additionally, such efforts serve to minimize disparities and uphold the integrity of research. In this review, we have laid out recommendations for laboratories to overcome these PN discrepancies when working with cancer cell lines.

Combination of 3PO analog PFK15 and siPFKL efficiently suppresses the migration, colony formation ability, and PFK-1 activity of triple-negative breast cancers by reducing the glycolysis.

Among all the subtypes of breast cancer, triple-negative breast cancer (TNBC) has been associated with the worst prognosis. Recently, for many solid tumors (including breast cancer) metabolic reprogramming has appeared as a cancer cell hallmark, and the elevated glycolytic pathway has been linked to their aggressive phenotype. In the present study, we evaluated the prognostic and therapeutic relevance of PFKFB3 (6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase) in TNBCs. Prognostic significance of PFKFB3 expression was evaluated in overall breast cancers as well as in TNBCs. PFKFB3 inhibitor (3PO potent analogue i.e., PFK15) cytotoxicity in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was analyzed using an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cancer cell physiological characteristics like clonogenicity and migration were also investigated after PFK15 treatment. As fructose-2,6-bisphosphate (F-2,6-BP), has been associated with increased PFK-1 activity, the effect of PFKFB3 inhibition by PFK15 was investigated on two major isoforms of phosphofructokinase-1 (PFK-1) in breast cancer, that is, phosphofructokinase-platelet type (PFKP) and phosphofructokinase-liver type (PFKL) (relevant to breast cancer). For PFKL inhibition, the siRNA approach was used. PFKFB3 expression was significantly correlated with inferior overall survival in breast cancer patients including TNBCs. PFK15 treatment in TNBC cells (i.e., MDA-MB-231 and MDA-MB-468) resulted in a decreased PFKP expression, thereby leading to reduced colony formation ability, migration rate, and extracellular lactate levels. However, to our surprise PFK15 treatment in both TNBC cells also resulted in elevated PFKL levels. Our results demonstrated that the combinatorial inhibition of PFK15 with siPFKL was more effective in TNBC cells, as it led to a decrease in colony formation ability, migration rate, extracellular lactate levels, and PFK-1 activity when compared with individual treatments. Using bona fide PFKFB3 inhibitor, that is, AZ67, we further show that AZ67 treatment to TNBC cells has no effect either on the expression of PFKP and PFKL, or on the lactate production. In summary, our present in vitro study demonstrated that 3PO derived PFK15 mechanism of action is totally different from AZ67 in TNBC cells. However, we advocate that the PFK15-mediated inhibition (along with PFKL) on the TNBCs migration, colony formation, and PFK-1 activity can be further explored for the therapeutic advantage of TNBC patients.

Improving the performance status in advanced non-small cell lung cancer patients with chemotherapy (ImPACt trial): a phase 2 study.

PURPOSE: This phase II trial is designed to test whether the performance status (PS) of metastatic non-small cell lung cancer (mNSCLC) patients (pts) can improve with chemotherapy if their poor PS (Eastern Cooperative Oncology Group (ECOG) PS of ≥ 2) is due to disease burden rather than comorbidities. METHODS: Age18-65 years, Charlson's comorbidity index < 9, serum albumin ≥ 3.5 g/dl, adequate bone marrow and organ function, & ECOG PS ≥ 2 as judged by the worst score of three independent physicians were administered 3 doses of weekly paclitaxel at 60 mg/m2/dose. The primary endpoint was an improvement in ECOG PS by 1 point at 4 weeks; others: toxicity (CTCAE v 5.0), quality of life (QoL) assessment at baseline and 4 weeks by EORTC QLQ-C30 and EORTC QLQ-LC13. Optimal Simon's 2-stage design was used. RESULTS:  Forty-six patients were included with a median age of 56 years (interquartile range, IQR 54-59), 12 (26%) had comorbid conditions, and 87% with ECOG PS 3/4. PS improved in 11 pts at 4 weeks and in 7 beyond this time point. Grade 3/4 toxicities are seen in 20% (most common: anemia and diarrhea). At a median follow-up of 4.8 m (95% CI 3.27-14.9), the median progression-free survival and overall survival were 3.3 months (95% CI 2.36-5.6) and 6.8 months (95% CI 2.47-8.8), respectively. QoL improved for global QoL, role functioning, pain, dyspnea, insomnia, pain in the chest, pain in other parts, and worsened for alopecia and sore mouth. CONCLUSIONS:  Abbreviated chemotherapy is a useful, well-tolerated strategy in carefully selected poor PS mNSCLC patients that can improve PS and QoL. CLINICAL TRIAL: Clinical trial information: CTRI/2020/01/022617.

Essential role of aerobic glycolysis in epithelial-to-mesenchymal transition during carcinogenesis.

Epithelial-to-mesenchymal transition (EMT) confers the most lethal characteristics to cancer cells i.e., metastasis and resistance to chemo-and-radio-therapy, and therefore exhibit an appealing target in the field of oncology. Research in the past decade has demonstrated the crucial role of aerobic glycolysis in EMT, which is generally credited as the glucose metabolism for the creation of biomass such as fatty acids, amino acids, and nucleotides thereby providing building blocks for limitless proliferation. In the present review, apart from discussing EMT's evident role in the metastatic process and cancer stemness, we also talked about the vital role of glycolytic enzymes viz. GLUTs, HKs, PGI, PFK-1, aldolase, enolase, PK, LDHA, etc. in the induction of the EMT process in cancerous cells.

Randomized double-blind, placebo-controlled study of topical diclofenac in the prevention of hand-foot syndrome in patients receiving capecitabine (the D-TORCH study).

INTRODUCTION: Hand-foot syndrome (HFS) is a common cutaneous side effect of capecitabine therapy. Apart from oral cyclooxygenase-2 (COX-2) inhibitor (celecoxib), there are no proven strategies for the prevention of HFS. However, celecoxib is associated with significant cardiotoxicity. To date, no study has evaluated the role of topical COX inhibitor, diclofenac. In this study, we aim to compare topical 1% diclofenac gel with placebo in the prevention of capecitabine-induced HFS. METHODS: This is a randomized, placebo-controlled, double-blind, parallel-group superiority trial: the Diclofenac Topical in Reducing Capecitabine induced HFS (D-TORCH) study. A total of 264 patients with breast and gastrointestinal malignancies will be randomly allocated (stratified by sex and type of therapy [monotherapy or combination regimen with capecitabine]) to receive either 1% topical diclofenac or placebo that will be applied over the palmar and dorsal surface of the hands twice daily whilst taking capecitabine for 12 weeks. The patients will be followed up until the end of four cycles. The primary objective of this study is to compare the effect of topical diclofenac with placebo in preventing HFS (incidence of NCI CTCAEv5.0 grade 2 or higher HFS). The secondary objective is to compare the effect of topical diclofenac with placebo on preventing all grades of HFS (incidence of NCI CTCv5.0 all grade HFS), time to develop HFS (from the start of capecitabine), patient-reported outcomes (PROs) (HF-HRQoL questionnaire), adherence with the application (self-reported), capecitabine dose changes (number of patients with dose modifications due to HFS) and safety profile (NCICTCv5.0 all grade HFS) DISCUSSION: The D-TORCH study aims to determine if 1% topical diclofenac reduces the incidence of grade 2 or higher HFS in patients receiving capecitabine. To date, there have been a lot of trials for hand-foot syndrome prevention using agents like pyridoxine, vitamin E, carvedilol, and various polyherbal formulations, but none has been found successful. If the trial meets the primary end point, 1% topical diclofenac will be the new standard of care for HFS prevention. TRIAL REGISTRATION: Clinical Trials Registry of India  CTRI/2021/01/030592 . Prospectively registered on January 19, 2021.

Bendamustine in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: A phase II trial.

Treatment of patients with resistant/refractory multiple myeloma (MM) is an unmet need. In this phase II study, we evaluated the role of bendamustine, pomalidomide and dexamethasone combination in this setting. Between February 2020 and December 2021, 28 patients were recruited. Patients received bendamustine 120 mg/m2 day 1, pomalidomide 3 mg days 1-21, and dexamethasone 40 mg days 1, 8, 11, 22, regimen given for a maximum of six cycles. The median (range) age of the patients was 54 (30-76) years and 15 (53.6%) were males. Patients had received a median (range) of three (two-six) prior lines and 85.7% were refractory to both lenalidomide and bortezomib. The primary end-point was the overall response rate (ORR) defined as ≥partial response after at least three cycles. Secondary objectives were toxicity, progression-free survival (PFS), time to progression and overall survival (OS). An intent-to-treat analysis was done. An ORR of 57.6% was achieved. Patients with extramedullary myeloma had a better response rate. At a median follow-up of 8.6 months, the median PFS and OS were 6.2 and 9.7 months respectively. Toxicity was manageable; mainly haematological (neutropenia, 46.4%; anaemia, 42.8%; and thrombocytopenia, 7.1%). Bendamustine, pomalidomide and dexamethasone could be a novel combination for the heavily pretreated, lenalidomide-refractory myeloma population.

Quercetin Impairs HuR-Driven Progression and Migration of Triple Negative Breast Cancer (TNBC) Cells.

In the present study, we have explored the prognostic value of HuR gene as well as protein in breast cancers. Furthermore, we have also investigated the HuR therapeutic relevance in TNBCs, which is an aggressive breast cancer subtype. Using an online meta-analysis tool, we found that HuR protein overexpression positively correlates with reduced overall survival of TNBC patients (p = 0.028). Furthermore, we demonstrated that the TNBC breast cancer cell lines i.e., MDA-MB-231 and MDA-MB-468 are good model systems to study HuR protein, as they both exhibit a significant amount of cytoplasmic HuR (active form). Quercetin treatment significantly inhibited the cytoplasmic HuR in both TNBC cell lines. By using specific HuR siRNA, we established that quercetin-mediated inhibition of adhesion and migration of TNBC cells is dependent on HuR. Upon analyzing adhesion proteins i.e., ß-catenin and CD44, we found that quercetin mediated effect on TNBC adhesion and migration was through the HuR-ß-catenin axis and CD44, independently. Overall, the present results demonstrate that elevated HuR levels are associated with TNBC progression and relapse, and the ability of quercetin to inhibit cytoplasmic HuR protein provides a rationale for using it as an anticancer agent for the treatment of aggressive TNBCs.Supplemental data for this article is available online at at 10.1080/01635581.2021.1952628.

Publication Charges Associated with Quality Open Access (OA) Publishing and Its Impact on Low Middle Income Countries (LMICs), Time to Reframe Research Policies.

Dissemination of the scientific literature is as paramount as scientific studies. Scientific publishing has come a long way from localized distribution of few physical copies of journal to widespread and rapid distribution via internet in the 21st century. The evolution of open excess (OA) publishing which has rapidly evolved in last two decades has its heart at the right place with the ultimate goal being timely, and rapid distribution of published scientific work to a wider scientific community around the world and thus ultimately promoting scientific knowledge in global sense. However, quality OA publishing of cancer research involve an average publishing fee of around 1,500 USD which poses a challenge for Low middle income countries (LMICs), where per capita income is low. This has led to deterioration of science in LMICs in the form of publication in Cheap OA predatory journals for sake of securing academic promotions as well as authors ending up paying exorbitant publishing charges out of pocket to get their quality scientific work published. In countries like India and other LMICs, the funding agencies and institution have so far not addressed this problem. Here we assess the framework of open access publishing in LMICs like India and what are the steps which can be taken to facilitate open access publishing in LMICs.

Dihydrotanshinone-I modulates Epithelial Mesenchymal Transition (EMT) Thereby Impairing Migration and Clonogenicity of Triple Negative Breast Cancer Cells.

BACKGROUND: Salvia miltiorrhiza Bunge (Danshen), has been used for its therapeutic value in Traditional Chinese Medicine (TCM), for almost a thousand years. Dihydrotanshinone-I (DHTS) is a lipophilic compound isolated from the plant Salvia miltiorrhiza that has been shown to induce anti-proliferative and apoptotic effects on breast cancer cells. In the present study, we investigated the anti-migratory effect of DHTS on TNBC cell lines by studying the Epithelial Mesenchymal Transition (EMT) changes. METHODS: IC50 values for DHTS in TNBC breast cancer cells were either discovered by literature search or by performing MTT assay. DHTS effect on EMT markers (viz. CD44, E-cadherin, Vimentin, N-cadherin, and active ß-catenin) was studied using western blotting. Association between EMT and migration was further carried out in DHTS treated TNBC cells by wound healing assay. Cancer stemness and proliferation potential were further accessed using colony formation assay. RESULTS: MTT assay revealed IC50 of MDA-MB-468 cells at 2 µM for 24 h. Subsequently, DHTS treatment in TNBC cell lines (MDA-MB-468 and MDA-MB-231) led to decrease in mesenchymal markers i.e. vimentin, N-cadherin and, active ß-catenin. DHTS treated MDA-MB-468 cells showed a decrease in adhesion protein CD44 and an increase in epithelial protein E-cadherin. Additionally, a decrease in EMT potential was positively associated with the inhibition of migration and clonogenic potential in DHTS treated TNBC cells. CONCLUSION: In this study, we have demonstrated for the first time that DHTS has the potential to inhibit the migration and clonogenicity of highly aggressive TNBC cells by obstructing Epithelial to Mesenchymal Transition.

Metabolic changes in triple negative breast cancer-focus on aerobic glycolysis.

Among breast cancer subtypes, the triple negative breast cancer (TNBC) has the worst prognosis. In absence of any permitted targeted therapy, standard chemotherapy is the mainstay for TNBC treatment. Hence, there is a crucial need to identify potential druggable targets in TNBCs for its effective treatment. In recent times, metabolic reprogramming has emerged as cancer cells hallmark, wherein cancer cells display discrete metabolic phenotypes to fuel cell progression and metastasis. Altered glycolysis is one such phenotype, in which even in oxygen abundance majority of cancer cells harvest considerable amount of energy through elevated glycolytic-flux. In the present review, we attempt to summarize the role of key glycolytic enzymes i.e. HK, Hexokinase; PFK, Phosphofructokinase; PKM2, Pyruvate kinase isozyme type 2; and LDH, Lactate dehydrogenase in TNBCs, and possible therapeutic options presently available.