Differential host responses to COVID-19: Unraveling the complexity.

These diverse outcomes of Covid-19 are influenced by various factors including age, gender, underlying health conditions, immune responses, viral variants, external factors, and overall quality of life. Demographic analysis of patients aged 0-18 years experienced mild to moderate cases, above 55 years with co-morbidities, were more severely affected.COVID-19 incidence was higher in males (58 %) & (42 %) in females. The reduced expression of Toll-like receptors (TLR) in severe and critical patients is a crucial determinant. This reduced TLR expression is primarily attributed to the dominance of the PLpro viral protein of COVID-19. Disease enrichment analysis highlights the long-term impact of COVID-19, which can lead to post-recovery complications such as hypertension, diabetes, cardiac diseases, and brain ischemia in Covid-19 patients. In conclusion, a comprehensive strategy targeting key factors like PLpro, TLR, and inflammatory cytokines such as IL-1 and IL-6 could offer an effective approach to mitigate the devastating effects of COVID-19.

MicroRNA signatures differentiate types, grades, and stages of breast invasive ductal carcinoma (IDC): miRNA-target interacting signaling pathways.

BACKGROUND: Invasive ductal carcinoma (IDC) is the most common form of breast cancer which accounts for 85% of all breast cancer diagnoses. Non-invasive and early stages have a better prognosis than late-stage invasive cancer that has spread to lymph nodes. The involvement of microRNAs (miRNAs) in the initiation and progression of breast cancer holds great promise for the development of molecular tools for early diagnosis and prognosis. Therefore, developing a cost effective, quick and robust early detection protocol using miRNAs for breast cancer diagnosis is an imminent need that could strengthen the health care system to tackle this disease around the world. METHODS: We have analyzed putative miRNAs signatures in 100 breast cancer samples using two independent high fidelity array systems. Unique and common miRNA signatures from both array systems were validated using stringent double-blind individual TaqMan assays and their expression pattern was confirmed with tissue microarrays and northern analysis. In silico analysis were carried out to find miRNA targets and were validated with q-PCR and immunoblotting. In addition, functional validation using antibody arrays was also carried out to confirm the oncotargets and their networking in different pathways. Similar profiling was carried out in Brca2/p53 double knock out mice models using rodent miRNA microarrays that revealed common signatures with human arrays which could be used for future in vivo functional validation. RESULTS: Expression profile revealed 85% downregulated and 15% upregulated microRNAs in the patient samples of IDC. Among them, 439 miRNAs were associated with breast cancer, out of which 107 miRNAs qualified to be potential biomarkers for the stratification of different types, grades and stages of IDC after stringent validation. Functional validation of their putative targets revealed extensive miRNA network in different oncogenic pathways thus contributing to epithelial-mesenchymal transition (EMT) and cellular plasticity. CONCLUSION: This study revealed potential biomarkers for the robust classification as well as rapid, cost effective and early detection of IDC of breast cancer. It not only confirmed the role of these miRNAs in cancer development but also revealed the oncogenic pathways involved in different progressive grades and stages thus suggesting a role in EMT and cellular plasticity during breast tumorigenesis per se and IDC in particular. Thus, our findings have provided newer insights into the miRNA signatures for the classification and early detection of IDC.

MicroRNA Signatures in Blood or Bone Marrow Distinguish Subtypes of Pediatric Acute Lymphoblastic Leukemia.

OncomiRs are microRNAs that are associated with early onset of specific cancers. To identify microRNAs involved in pediatric acute lymphoblastic leukemia (ALL) subtypes T-ALL and B-ALL, peripheral blood and bone marrow samples were independently subjected to microarray analysis using two different high-fidelity array platforms. The unique and common gene signatures from both arrays were validated by TaqMan individual assays in 100 pediatric ALL samples. Survival studies were carried out in the test set and validation set with 50 randomly selected samples in each set. MicroRNA expression profile revealed characteristic signatures for distinguishing T and B lineages and identified 51 novel microRNAs in pediatric ALL. Interestingly, the present study also revealed endogenous similarities and differences between blood and bone marrow within each ALL subtype. When Cox regression analysis was carried out with these identified microRNAs, 11 of them exhibited expression levels significantly correlated with survival. Validation of some of the common and relevant microRNAs from both arrays showed that their targets are involved in key oncogenic signaling pathways. Thus, this study suggests that microRNAs have the potential to become important diagnostic tools for identification and monitoring clinical outcomes in ALL patients.

Role of semi-purified andrographolide from Andrographis paniculata extract as nano-phytovesicular carrier for enhancing oral absorption and hypoglycemic activity.

Objective: Andrographis paniculata is a well-known medicinal plant in Southeast Asia, India and China. The plant contains andrographolide (AN), a very important phytochemical used in various health problems. However, AN is low in oral absorption bioavailability of AN due to the rapid clearance and high protein binding capacity. Methods: The present study was aimed to develop a nano-phytovesicular formulation of semi-purified AN extracts from a naturally occurring phospholipid (soya phosphatidylcholine) in order to increase the oral absorption and antihyperglycemic activity in rats. Results: The nano-phyto vesicle of semi-purified AN extracts equivalent to 25 mg /kg AN significantly protected the hyperglycemic condition of rats. The in vitro and in vivo experiments results proved that the nano- phytovesicular system of plant extracts containing AN produced better oral absorption, bioavailability and improved antihyperglycemic activity compared with that of free AN at dose of 50 mg/kg. Conclusion: Hence, the prepared semi-purified extract nano-phytovesicular system is helpful in solving the problem of rapid clearance of AN.

PCR Amplifiable DNA from Breast Disease FFPE Section for Mutational Analysis.

Formalin-fixed paraffin-embedded (FFPE) tissue specimens have been a staple of research, providing precious resources for molecular and genomic studies. However, the biggest challenge is the extraction of high-quality DNA from FFPE tissues, given that the integrity of DNA is critically affected by formalin fixation. Formaldehyde induces crosslinks in DNA that renders single or double-stranded DNA breaks. Such breaks cause extensive fragmentation that directly influences the quality of DNA purified and the number of templates available for PCR amplification. Thus, protocol for DNA purification from FFPE tissues must effectively extract highly fragmented DNA and reverse cross-linking caused by formalin fixation. DNA extraction methods available in the literature were selected and modified at different stages to optimize a protocol that extracts DNA of sufficient quality and fragment size to be detectable by PCR. Archived FFPE tissues belonged to patients with triple negative breast cancer (TNBC) and benign breast disease were used for the protocol optimization. The best optimized protocol was then used to amplify Exon 4 region of Proviral integration site for Moloney murine leukemia virus1 (Pim1) kinase gene to analyze any probable somatic mutations both in TNBCs and benign breast diseases. Of the 12 different protocols developed, best quality DNA in terms of fragment size and purity was obtained when Tween20 lysis buffer was used for both deparaffinization and overnight digestion along with high salt precipitation. Optimized protocol was then validated by extracting DNAs from 10 TNBCs and 5 benign breast disease specimens with consistent purity and fragment size. PCR amplification and subsequent Sanger's sequencing revealed the presence of mutations in the Exon 4 region of Pim1 kinase. Deparaffinization and overnight digestion in Tween20 lysis buffer along with high salt precipitation yielded the best quality PCR amplifiable DNA for mutational analysis.

Perioperative myocardial infarction in a young adult after percutaneous nephrolithotomy.

The causes of myocardial infarction in a young adult can be divided into four groups: (1) atherosclerosis, (2) nonatherosclerosis, (3) hypercoagulable states, and (4) substance abuse. We present here a case of the 29-year-old male patient who developed myocardial infarction after undergoing percutaneous nephrolithotomy. Prompt diagnosis and timely intervention salvaged his myocardium.

Climato-environmental influence on breeding phenology of native catfishes in River Ganga and modeling species response to climatic variability for their conservation.

The main objectives of the present study were to quantify the environmental, especially temperature and rainfall, effects on breeding phenology of selected catfish species and to predict changes in breeding phenology of the selected species in relation to climatic variability for the Ganga River Basin. The study showed that changes in rainfall pattern may have the most profound effect on gonad maturation and breeding of Mystus tengara and Mystus cavasius followed by the effect of increased water temperature due to rising air temperature. Indication of region-specific adaptation was noticed in reproductive phenology of Eutropiichthys vacha based on local trends of warming climate. The other habitat parameters, such as dissolved oxygen, alkalinity, nitrate, and phosphate, were correlated with gonad maturity and spawning. Climatic variability may bring region-specific changes in breeding phenology of fish species in the Ganga River. Under a warming climate, changes in precipitation pattern manifested into riverine flow pulse may be the key driver in dictating breeding phenology. Our study indicates E. vacha as a climate sensitive species that may be selected as a target species for climate change impact studies.

Biodrug Suppresses Breast and Colorectal Cancer in Murine Models.

RNA interference (RNAi) remains one of the most promising and emerging strategies for the effective cancer treatment due to its high target specificity and greater potency. However, it is hindered due to lack of appropriate targeting technologies. Therefore, there is an imminent need to develop specific and robust delivery systems for successful gene silencing. Nanotechnology-based strategies have been in place to combat the shortcomings associated with viral-based delivery systems. Herein we describe protocols for successful in vitro and in vivo delivery of gene-specific nucleic acids such as siRNAs and shRNAs using PEI-PGMA nanoparticles for efficient cancer therapy.

Environmental impact on the onset of hypertension-induced end-stage renal disease.

This study intends to assess the impact of environmental factors on the onset of hypertension-induced end-stage renal disease (ESRD) and to compare the level of oxidative stress with nonhypertensive diabetic ESRD. ESRD patients were evaluated along with healthy controls through questionnaire for demographic, nutritional and lifestyle variables. Oxidants were measured along with antioxidants. Multiple linear regression (MLR) models were applied to analyze association of studied variables with oxidants and antioxidants. Most of the hypertensive nephrosclerotic patients were residing in locality that was either closer to industrial belt or polluting water bodies, belonging to low socioeconomic status that invariably affected their lifestyle and nutritional status. Hypertensive ESRD patients showed more pronounced oxidative stress than diabetic ESRD. Several of the studied variables were significantly associated with oxidants and antioxidants. Demographic, nutritional and lifestyle variables appeared to have suggestive effect on the onset of hypertensive nephrosclerosis.

Benchmarking pre-spawning fitness, climate preferendum of some catfishes from river Ganga and its proposed utility in climate research.

The concept of threshold condition factor (Fulton), beyond which more than 50% of the female fish population may attain readiness for spawning coined as pre-spawning fitness (K spawn50), has been proposed in the present article and has been estimated by applying the non-parametric Kaplan-Meier method for fitting survival function. A binary coding strategy of gonadal maturity stages was used to classify whether a female fish is "ready to spawn" or not. The proposed K spawn50 has been generated for female Mystus tengara (1.13-1.21 units), M. cavasius (0.846-0.945 units), and Eutropiichthys vacha (0.716-0.799 units). Information on the range of egg parameters (fecundity, egg weight, egg diameter) expected at the pre-spawning stage was also generated. Additional information on species-specific thermal and precipitation window (climate preferendum) within which K spawn50 is attained was also generated through the LOESS smoothing technique. Water temperatures between 31 and 36 °C (M. tengara), 30 and 32 °C (M. cavasius), and 29.5 and 31 °C (E. vacha) and monthly rainfall between 200 and 325 mm (M. tengara), > 250 mm (M. cavasius), and around 50 mm and between 350 and 850 mm (E. vacha) were found to be optimum for attainment of K spawn50. The importance of parameterization and benchmarking of K spawn50 in addition to other conventional reproductive biology parameters has been discussed in the present article. The purposes of the present study were fulfilled by generating baseline information and similar information may be generated for other species replicating the innovative methodology used in this study.

A randomized controlled study between fentanyl and Butorphanol with low dose intrathecal bupivacaine to facilitate early postoperative ambulation in urological procedures.

INTRODUCTION: Opioids are widely used in conjunction with local anesthetics as they permit the use of lower dose of local anesthetics while providing adequate anesthesia and analgesia. It both provides adequate anesthesia as well as lower drug toxicity neuraxial administration of opioids in conjunction with local anesthetics improves the quality of intraoperative analgesia and prolongs the duration of postoperative analgesia. Bupivacaine is the most commonly used drug for subarachnoid block due to its lesser side effects. The present study was conducted to decrease the overall dose of local anesthetics with opioid combination for urological procedure with respect to quality of anesthesia and recovery with patient's satisfaction. MATERIALS AND METHODS: The study population was randomly allocated by computer generated table into two groups; Group A: 5 mg 0.5% bupivacaine + 25 mcg and Group B: 5 mg 0.5% bupivacaine + 25 mg butorphanol. RESULTS: Highest level of sensory block was T9 and T8 with the fentanyl group and butorphanol group, respectively. The onset of sensory block was early in fentanyl group than butorphanol group. Duration of both sensory and motor block was significantly higher in butorphanol group. There was no incidence of itching in both groups. There were two patients in fentanyl group and one in butorphanol with hypotension for which injection mephentermine was given. Two patients in fentanyl group complained of nausea and vomiting, for which injection ondansetron was given. One patient complained of pain in fentanyl group for which injection propofol with injection fentanyl was supplemented. CONCLUSION: Low-dose bupivacaine with butorphanol group was devoid of any side effects in the present study but low dose bupivacaine in addition with fentanyl is superior in terms of early postoperative recovery resulting in early discharge and better outcome in comparison to bupivacaine and butorphanol group, which is beneficial in elderly patients with comorbidity.

Clinical efficacy of platelet rich plasma in combination with methotrexate in chronic plaque psoriatic patients.

Psoriasis affects up to 3% of the world's population or more than 125 million people. There is an urgent need for new treatment strategy, as up to 50% of patients are not satisfied with current therapies. We evaluated the combined efficiency of platelet rich plasma (PRP) and methotrexate (MTX) in the management of patients with plaque psoriasis. Twenty-one patients with chronic plaque psoriasis were recruited in the study. Sixteen patients were assigned into combinational treatment group (PRP + MTX) and monotherapy group (MTX alone) consisted of five patients. All patients in combinational therapy received autologous PRP in their first sitting and subsequently followed with folitrax-15 for 4 weeks, while patients in monotherapy group received only folitrax-15, all patients received intra-lesional injections. Digital photograph, Psoriasis Area Severity Index (PASI) score and adverse events were recorded at weeks 0, 4, 8, 12 and 16 and were evaluated by three investigators independently. Patients treated with PRP/MTX showed substantial improvement in term of reduction in erythema, induration and desquamation at each visit and was effectively cleared off psoriasis at week 16. Combination treatment of PRP with MTX was well tolerated by all patients without any serious adverse events.

Fluorescent magnetic iron oxide nanoparticles for cardiac precursor cell selection from stromal vascular fraction and optimization for magnetic resonance imaging.

Fluorescent magnetic iron oxide nanoparticles have been used to label cells for imaging as well as for therapeutic purposes. The purpose of this study was to modify the approach to develop a nanoprobe for cell selection and imaging with a direct therapeutic translational focus. The approach involves physical coincubation and adsorption of superparamagnetic iron oxide nanoparticle-polyethylene glycol (SPION-PEG) complexes with a monoclonal antibody (mAb) or a set of antibodies. Flow cytometry, confocal laser scanning microscopy, transmission electron microscopy, iron staining, and magnetic resonance imaging were used to assess cell viability, function, and labeling efficiency. This process has been validated by selecting adipose tissue-derived cardiac progenitor cells from the stromal vascular fraction using signal regulatory protein alpha (SIRPA)/kinase domain receptor (KDR) mAbs. These markers were chosen because of their sustained expression during cardiomyocyte differentiation. Sorting of cells positive for SIRPA and KDR allowed the enrichment of cardiac progenitors with 90% troponin-I positivity in differentiation cultures. SPION labeled cardiac progenitor cells (1×10(5) cells) was mixed with gel and used for 3T magnetic resonance imaging at a concentration, as low as 12.5 µg of iron. The toxicity assays, at cellular and molecular levels, did not show any detrimental effects of SPION. Our study has the potential to achieve moderate to high specific cell selection for the dual purpose of imaging and therapy.

Potential of capsaicin-loaded transfersomes in arthritic rats.

In the present study, the biopotential of capsaicin (an active principle of capsicum) as a topical antiarthritic agent was studied in arthritic rats. Transfersomal vesicular system was employed for the topical administration of capsaicin in experimental rats. The characterization of prepared capsaicin-loaded transfersomes reveals their nano size (94 nm) with negative surface charge (-14.5 mV) and sufficient structural flexibility, which resulted in 60.34% entrapment efficacy, penetration across the biomembrane (220 µm) and 76.76% of drug release from vesicular system in 24 h in their intact form as evident from confocal laser scanning micrographic study. Results of transfersomal nanoformulation (capsaicin loaded, test) were compared with that of conventional gel formulation available in the market (Thermagel, standard), with an aim to assess the antiarthritic efficacy of our prepared capsaicin-loaded transfersomal formulation. In vivo antiarthritic activity study shows that our formulation possesses superior inhibitory activity than the marketed Thermagel formulation at the same dosage level, which could probably be due to the lesser permeability of Thermagel across the dermal barriers compared to our specially designed transfersomal delivery system. Moreover, the better tolerance of prepared vesicular formulation in biological system further enlightens the suitability of the transfersomal vesicle to be used as a novel carrier system for the topical administration of such highly irritant substance.

OncomiRdbB: a comprehensive database of microRNAs and their targets in breast cancer.

BACKGROUND: Given the estimate that 30% of our genes are controlled by microRNAs, it is essential that we understand the precise relationship between microRNAs and their targets. OncomiRs are microRNAs (miRNAs) that have been frequently shown to be deregulated in cancer. However, although several oncomiRs have been identified and characterized, there is as yet no comprehensive compilation of this data which has rendered it underutilized by cancer biologists. There is therefore an unmet need in generating bioinformatic platforms to speed the identification of novel therapeutic targets. DESCRIPTION: We describe here OncomiRdbB, a comprehensive database of oncomiRs mined from different existing databases for mouse and humans along with novel oncomiRs that we have validated in human breast cancer samples. The database also lists their respective predicted targets, identified using miRanda, along with their IDs, sequences, chromosome location and detailed description. This database facilitates querying by search strings including microRNA name, sequence, accession number, target genes and organisms. The microRNA networks and their hubs with respective targets at 3'UTR, 5'UTR and exons of different pathway genes were also deciphered using the 'R' algorithm. CONCLUSION: OncomiRdbB is a comprehensive and integrated database of oncomiRs and their targets in breast cancer with multiple query options which will help enhance both understanding of the biology of breast cancer and the development of new and innovative microRNA based diagnostic tools and targets of therapeutic significance. OncomiRdbB is freely available for download through the URL link http://tdb.ccmb.res.in/OncomiRdbB/index.htm.

Potential wound healing activity of the ethanolic extract of Solanum xanthocarpum schrad and wendl leaves.

The present work objective are to investigate indigenous plants used in wound healing in India, we hereby reported our findings related to wound healing activities of plant Solanum xanthocarpum Schrad and Wendl (Solanaceae) from some in vitro and in vivo model studies. The plant ethanolic extracts of the leaves of Solanum xanthocarpum was identified qualitative phytochemical constituents and tested wound healing activity. The important secondary metabolites alkaloid, glycosides, saponins, carbohydrates, tannins, phenolic compounds, protein, and fats were identified in extracts. Solanum xathocarpum leaves ethanolic extract showed wound healing activity significantly in the excision and incision wound model in rats on topical application. The animals were divided into five groups with six rats in each group. Topically applied 10% w/v of plant Solanum xanthocarpum leaves extracts in saline taking Silver Sulphadizine ointment as standard. The results showed that ethanolic extract of Solanum xathocarpum leaves on topical application was reduced the epithelization period from 25.30±0.23 to 19.75±0.28 days control and ethanol extract respectively along with a marked decrease in the scar area from 53.88±0.42 to 37.76±0.17 mm2 control and ethanol extract respectively. Significant increase in tensile strength and hydroxyproline content of plant extract were also observed and compared to the control and silver sulphadiazine. The above result revealed that the ethanol extract has remarkable wound healing potency and appear to justify the traditional use of Solanum xanthocarpum in wound healing in India and offer a scientific support to the treatment of traditional healers.

Effects of atorvastatin and rosuvastatin on high-sensitivity C-reactive protein and lipid profile in obese type 2 diabetes mellitus patients.

OBJECTIVE: To evaluate and compare the effects on high-sensitivity C-reactive protein (hs-CRP) levels and lipid profile of atorvastatin and rosuvastatin in obese type 2 diabetes mellitus (T2DM) patients. MATERIALS AND METHODS: A total of 40 subjects with 20 in each group were randomly allocated to two groups. Group 1 patients received atorvastatin and that of Group 2 rosuvastatin treatment for 6 months. The patients were administered atorvastatin (40-80 mg) and rosuvastatin(10-40 mg) in accordance to their LDL-C status as per NCEP-ATP III guidelines. The parameters studied were, hs-CRP and lipid profile comprising LDL-C, HDL-C, TG and TC. RESULTS: Results obtained from the study, clearly indicate that atorvastatin (A) as well as rosuvastatin(R) have significant effect on lowering of hs-CRP levels (for A P=0.001; for R P=0.002), reducing LDL-C levels (for A P=0.008; for R P=0.001), elevating HDL-C levels (for A P=0.02; for R P=0.001) along with reducing TC (for A P=0.003; for R P=0.002) and TG (for A P=0.000; for R P=0.000) levels in obese T2DM patients. It is also seen that there is no significant (P>0.05) difference in effect of atorvastatin and rosuvastatin in lowering of hs-CRP levels, elevating HDL-C levels and reducing TG levels in obese T2DM patients. However, percentage lowering of LDL-C (P=0.000) and TC (P=0.001) by rosuvastatin is to a greater extent than that caused by atorvastatin in these patients. CONCLUSIONS: Thus this study throws light on the fact that rosuvastatin should be preferred over atorvastatin in obese T2DM patients in whom LDL-C and TC levels are deviated from normal reference values. In rest of obese T2DM either of atorvastatin or rosuvastatin can be employed to lower hs-CRP levels, to elevate HDL-C levels or to reduce TG levels.

Treadmill exercise-dependent tumor growth retardation in T-cell lymphoma-bearing host displays gender dimorphism.

A number of previous investigations have reported that physical exercise renders immunopotentiating and antitumor therapeutic benefits to the tumor-bearing host. As these effects of physical exercise are mainly mediated through the modulation of hormonal and cytokine repertoire, it remains unclear if male and female tumor-bearing hosts show a gender-dependent differential response to the therapeutic action of physical exercise in tumor growth retardation. In the present investigation tumor growth retardation, following physical exercise was investigated in a gender-specific manner in a murine tumor model of a T-cell lymphoma designated as Dalton's lymphoma (DL). The results of the present investigation show that physical exercise of a tumor-bearing host on a treadmill results in a better retardation of tumor progression along with prolongation of survival time in male compared to female tumor-bearing host. Such gender dimorphism of the therapeutic benefits of physical exercise in tumor-bearing host was found to be associated with a gender-dependent variation in cell survival and induction of apoptosis in tumor cells. Moreover, expression of cell growth regulatory proteins-selectin, Hsp70, p53, CAD, SOCS, and IL-2 receptor-was found to vary in a gender-specific manner following physical exercise. The investigation also indicates the role of cytokines and macrophages in manifestation of gender dimorphism in the response of tumor-bearing mice to physical exercise. Thus, the observations of the present investigation suggest for the first time that the beneficial effects of physical exercise in a tumor-bearing host may be variable depending on the gender of the host.

Effect of physical exercise on tumor growth regulating factors of tumor microenvironment: implications in exercise-dependent tumor growth retardation.

Recently, we reported that treadmill exercise renders survival benefits in a murine tumor model of a transplantable lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), owing to an augmented apoptosis of tumor cells. However, the underlying the mechanisms of the same remained unclear with respect to the role alterations if any in the components of tumor microenvironment following physical exercise. Therefore, in the present we investigated the role of oxygen, pH, lactate and cytokines of tumor micro-environment associated with physical exercise-dependent alteration in the growth properties of tumor cells to explore their contribution in modulation of tumor. Physical exercise of tumor-bearing host resulted in a decreased angiogenesis in the vicinity of tumor. This was also found to be accompanied by a decrease in erythrocyte count and increase in the level of oxygen while the content of lactate showed a concomitant decrease in the tumor microenvironment along with normalization of pH. Moreover, physical exercise also resulted in an inhibition of VEGF expression which was correlated to an altered expression of cytokines: IL-1, IL-4, IL-10, TGF-beta and IFN-gamma. Ascitic fluid of tumor-bearing host subjected to physical exercise showed an increase in nitric oxide content along with an increase in the expression of inducible nitric oxide synthase (iNOS). The study discusses the possible role of the aforesaid alterations in constituents of tumor microenvironment of tumor-bearing host following physical exercise in retardation of tumor growth.

Chimeric and humanized anti-HM1.24 antibodies mediate antibody-dependent cellular cytotoxicity against lung cancer cells.

HM1.24 antigen (CD317) was originally identified as a cell surface protein that is preferentially overexpressed on multiple myeloma cells. Immunotherapy using anti-HM1.24 antibody has been performed in patients with multiple myeloma as a phase I study. The aim of this study was to evaluate the anti-tumor activity of mouse-human chimeric and humanized anti-HM1.24 monoclonal antibodies (mAbs) against lung cancer cells in vitro. Human peripheral blood lymphocytes and monocytes separated from mononuclear cells (PBMCs) were used as effector cells. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of chimeric and humanized anti-HM1.24 mAbs against lung cancer cells were determined by chromium-release assay. In some experiments, target or effector cells were pretreated with various cytokines. Chimeric and humanized anti-HM1.24 mAbs effectively induced ADCC against lung cancer cells mediated more efficiently by lymphocytes than monocytes. The cytotoxic activity correlated with the level of HM1.24 expression on lung cancer cells. Natural killer cells were identified as the major effector cells in ADCC mediated by the anti-HM1.24 mAb. The treatment of lymphocytes or monocytes with IL-2, IL-12, IL-15, M-CSF, or IFN-gamma significantly increased the ADCC activity. Moreover, the culture of lung cancer cells with IFN-beta or IFN-gamma augmented their susceptibility to ADCC and CDC. PBMCs from patients with lung cancer induced a level of ADCC comparable to that induced by PBMCs from healthy donors. Chimeric or humanized anti-HM1.24 mAbs have potential as a new therapeutic tool in lung cancer, and in combination with interleukins and interferons, could be useful for enhancing ADCC.