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Natural compounds obtained from plants are capable of garnering considerable attention from the scientific community, primarily due to their ability to check and prevent the onset and progress of cancer. These natural compounds are primarily used due to their nontoxic nature and the fewer side effects they cause compared to chemotherapeutic drugs. Furthermore, such natural products perform even better when given as an adjuvant along with traditional chemotherapeutic drugs, thereby enhancing the potential of chemotherapeutics and simultaneously reducing their undesired side effects. Curcumin, a naturally occurring polyphenol compound found in the plant , is used as an Indian spice. It regulates not only the various pathways of the immune system, cell cycle checkpoints, apoptosis, and antioxidant response but also numerous intracellular targets, including pathways and protein molecules controlling tumor progression. Many recent studies conducted by major research groups around the globe suggest the use of curcumin as a chemopreventive adjuvant molecule to maximize and minimize the desired effects and side effects of chemotherapeutic drugs. However, low bioavailability of a curcumin molecule is the primary challenge encountered in adjuvant therapy. This review explores different therapeutic interactions of curcumin along with its targeted pathways and molecules that are involved in the regulation of onset and progression of different types of cancers, cancer treatment, and the strategies to overcome bioavailability issues and new targets of curcumin in the ever-growing field of cancer.

BackgroundPrimary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, characterized by mononuclear cell infiltrates in the salivary and lacrimal glands, leading to glandular atrophy and dryness. Patient heterogeneity and lack of knowledge regarding its pathogenesis makes pSS a difficult disease to manage.MethodsAn exploratory analysis using mass cytometry was conducted of MAPK/ERK and JAK/STAT signaling pathways in peripheral blood mononuclear cells (PBMC) from 16 female medication free pSS patients (8 anti-Sjögren’s syndrome-related antigen A negative/SSA- and 8 SSA+) and 8 female age-matched healthy donors after stimulation with interferons (IFNs).ResultsWe found significant differences in the frequencies of memory B cells, CD8+ T central and effector memory cells and terminally differentiated CD4+ T cells among the healthy donors and patient subgroups. In addition, we observed an upregulation of HLA-DR and CD38 in many cell subsets in the patients. Upon IFNα2b stimulation, slightly increased signaling through pSTAT1 Y701 was observed in most cell types in pSS patients compared to controls, while phosphorylation of STAT3 Y705 and STAT5 Y694 were slightly reduced. IFNγ stimulation resulted in significantly increased pSTAT1 Y701 induction in conventional dendritic cells (cDCs) and classical and non-classical monocytes in the patients. Most of the observed differences were more prominent in the SSA+ subgroup, indicating greater disease severity in them.ConclusionsAugmented activation status of certain cell types along with potentiated pSTAT1 Y701 signaling and reduced pSTAT3 Y705 and pSTAT5 Y694 induction may predispose pSS patients, especially the SSA+ subgroup, to upregulated expression of IFN-induced genes and production of autoantibodies. These patients may benefit from therapies targeting these pathways.

Primary Sjögren's syndrome (pSS) is associated with polymorphisms and mRNA expression profiles that are indicative of an exaggerated innate and type I IFN immune response. Excessive activation potential of signaling pathways may play a role in this profile, but the intracellular signaling profile of the disease is not well characterized. To gain insights into potentially dysfunctional intracellular signaling profiles of pSS patients we conducted an exploratory analysis of MAPK/ERK and JAK/STAT signaling networks in peripheral blood mononuclear cells (PBMC) from 25 female pSS patients and 25 female age-matched healthy donors using phospho-specific flow cytometry. We analyzed unstimulated samples, as well as samples during a 4 h time period following activation of Toll-like receptor (TLR) 7 and 9. Expression levels of , and in PBMC were analyzed by real-time PCR. Cytokine levels in plasma were determined using a 25-plex Luminex-assay. Principal component analysis (PCA) showed that basal phosphorylation profiles could be used to differentiate pSS patients from healthy donor samples by stronger intracellular signaling pathway activation in NK and T cells relative to B cells. Stimulation of PBMC with TLR7 and -9 ligands showed significant differences in the phosphorylation profiles between samples from pSS patients and healthy donors. Including clinical parameters such as extraglandular manifestations (EGM), we observed stronger responses of NF-κB and STAT3 S727 in B cells from EGM-negative patients compared to EGM-positive patients and healthy controls. Plasma cytokine levels were correlated to the basal phosphorylation levels in these patients. In addition, 70% of the patients had a positive IFN score. These patients differed from the IFN score negative patients regarding their phosphorylation profiles and their plasma cytokine levels. In conclusion, we here report increased signaling potentials in peripheral B cells of pSS patients in response to TLR7 and -9 stimulation through STAT3 S727 and NF-κB that correlate with a type I IFN signature. Induction of these pathways could contribute to the generation of a type I IFN signature in pSS. Patients displaying elevated potentiation of STAT3 S727 and NF-κB signaling could therefore benefit from therapies targeting these pathways.

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson’s r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-β (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-β inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.

We investigated whether accelerated seismic strain release precedes large earthquakes occurring in and around the Sistan Suture Zone, Eastern Iran. Online catalogs of teleseismic events occurring post-1960 within the region 27.0°–37.0°N, 55.0°–65.0°E, report five M w > 7.0 earthquakes, namely, 1968 Dasht-e-Bayaz, 1978 Tabas, 1979 Khuli-Buniabad, 1981 Sirch and 1997 Zirkuh-e-Q’aenat events. We defined four earthquake test episodes, 1968–1978, 1978–1981, 1979–1981, and 1981–1997, with all catalogued intermediate events having magnitudes within 2.0 units that of the final large event. Using the 1968 event as the starting point, we investigated possible increased moderate earthquake activity patterns prior to the large events of 1978, 1981 and 1997 by examining if the cumulative Benioff strain released from such preceding events followed a power law time-to-failure. Our investigation seem to suggest that the 1978, 1981 and 1997 events (i) followed a period of accelerated moderate earthquake activity and (ii) the radius of their optimal critical region, R , scaled with their magnitude, M , according to the scaling law log R ∝ 0.36 M . Our suggestions conform to those proposed by similar investigations in varied seismotectonic regimes.

Landslide susceptibility zonation (LSZ) is necessary for disaster management and planning development activities in mountainous regions. A number of methods, viz. landslide distribution, qualitative, statistical and distribution-free analyses have been used for the LSZ studies and they are again briefly reviewed here. In this work, two methods, the Information Value (InfoVal) and the Landslide Nominal Susceptibility Factor (LNSF) methods that are based on bivariate statistical analysis have been applied for LSZ mapping in a part of the Himalayas. Relevant thematic maps representing various factors (e.g., slope, aspect, relative relief, lithology, buffer zones along thrusts, faults and lineaments, drainage density and landcover) that are related to landslide activity, have been generated using remote sensing and GIS techniques. The LSZ derived from the LNSF method, has been compared with that produced from the InfoVal method and the result shows a more realistic LSZ map from the LNSF method which appears to conform to the heterogeneity of the terrain.[PUBLICATION ABSTRACT]

Immune systems play a pivotal role in recognizing cancer and induce effective immune responses for their clearance. Avoidance of immune system is one of the major hallmarks in cancer progression that successively transforms immune surveillance (tumor eradication) to immune tolerance (tumor progression). Modulation of immune cells to harness the power of effective immune responses has been long-term goals for promising strategies of cancer immune therapy. Monoclonal antibodies, immune modulators, vaccines, immune checkpoint blockers are now widely used in cancer immunotherapy. Immunotherapy also provides supportive care against high-dose cancer chemotherapy regimens. Recently immunotherapy was adopted as one of the major approaches during bone marrow transplant of hematologic malignancy. Immune-based therapeutic strategies efficiently restrict tumor evasion and have also shown efficacy against multi-drug resistant cells, one of the most crucial complications in cancer treatment. Advances in immunology and understanding the roles of immune cells in cancer microenvironment have led to numerous specific strategies to boost immune components that successively dampen cancer progression. In this review, we have described several effective immune therapy strategies that target tolerogenic immune cells to become immunogenic and restore immune surveillance in cancer. Manipulation of immune cells by novel therapeutic strategies strive to induce antitumor immune responses by expanding effective anti-tumor T cell immune responses, evoking immune activation signaling and restraining regulatory pathway that established immune-tolerance. The future of cancer immunotherapy relies on a combination of these effective strategies to harness the immune power to restrict cancer advancement.

The National Capital Region (NCR) of India is exposed to high seismic hazard and risk due to a great earthquake in the central seismic gap of Himalaya and/or due to moderate-size earthquake within NCR. The high population density, rapid growth of infrastructure, and old engineering structures in the region make it more vulnerable to the human as well as economic loss due to moderate-size earthquakes also. The evaluation of seismic hazard is the first step to prepare a proper mitigation plan for the region. The aim of this paper is to evaluate the seismic hazard and risk due to moderate-size earthquakes in the vicinity of NCR. For this purpose, a suit of accelerograms have been generated from hypothetical moderate-size earthquakes ( M 5.5 and 6.0) in the region. A basic fault-plane solution is assumed for this purpose. The ranges of the different parameters like depth of focus and stress drop values have been used in order to examine the effect of these parameters on hazard. The accelerograms have been synthesized using two basic velocity models, one representing a hard site and the other a site with a significant low-velocity cover. These two velocity models represent the ridge area and trans-Yamuna river area in the NCR. The decay of peak ground acceleration (pga) values with distance is fast in trans-Yamuna region (with low-velocity surface layer of 100 m) as compared to that of ridge area (with low-velocity surface layer of 1 m). Also, the decay of pga becomes slower if we increase the depth of focus from 10 to 20 km. The response spectra (5% damping) of the synthetic accelerograms for the three periods T  = 0.4s, 0.75s, and 1.25s have been estimated and presented in the form of decay curves. The amplifications as a function of epicentral distance and stress drop have also been estimated. We note that the amplifications in 100-m layer case do not occur uniformly at all the distances, rather it is dependent on the angle of incidence of energy into the layers. The pga values are generally amplified by more than twice with increase in stress drop from 100 to 400 bars. The seismic exposure of the population in Delhi city has been presented. The results presented in this study may serve as an important input in the planning of mitigation and disaster management programs in the National Capital Region.

The NCR (National Capital Region) currently shows low level seismicity. However, according to the historical information, the region has faced two very large events, viz. the MMI XII (?) event in 893 (ref. 1) and the 1720 (ref. 2) event of MMI XI. Even relatively distant events have inflicted damage in Delhi3-5. This obviously sets up serious alarm regarding seismic hazard of the region. A repeat of the 1720 event now could be as calamitous, if not more than the 2001 Bhuj event. The calamitous, M 7.7. Gujarat earthquake of 26 January 2001 occurred in a region of low seismic activity. Thus a relatively low rate of small earthquakes does not necessarily equate to low seismic hazard.

The Bhuj earthquake of January 26th, 2001, induced wide spread liquefaction within the Kachch peninsula. It has been pointed out that inundation due to soil liquefaction was short lived in some parts than in others in the affected region. Several geological, seismological and hydrological factors would have cumulatively contributed to these observed changes. We simulate in this article, undrained or short-term change in pore pressure in a poroelastic half space, in response to a simplified model of the Bhuj earthquake source. We find that the regions of relatively shorter lived inundation due to soil liquefaction may fall in the region where pore pressure responsible for soil liquefaction attributable to strong ground shaking was counteracted by pore pressure changes due to undrained poroelastic effect and vice versa.[PUBLICATION ABSTRACT]